Roles of Chemokines in Influencing Tumor Microenvironment in Breast Cancer

Deok-Soo Son; Samuel Evans Adunyah

doi:10.5772/intechopen.1006828

Abstract

Chemokines regulate cell migration by binding to specific cell surface G protein-coupled receptors in development, physiology, and immune responses. Particularly in cancer, chemokines are involved in tumor cell growth, angiogenesis, cancer stem-like cell properties, metastasis, and directly and indirectly influencing tumor immunity and cancer progression. The chemokine signature in the tumor microenvironment affects immune contexture in tumor tissues and mutual communication between cells through the specific chemokine axis, contributing to cancer prognosis. The present chapter summarizes the role of chemokines in the tumor microenvironment in breast cancer, of which subtypes are classified as luminal A, luminal B, HER2-enriched, and basal-like, focusing on expression levels of chemokines and overall survivals in a chemokine-dependent manner and discovering the target chemokine axis. The outcome provides valuable information that improves the quality of life in patients with breast cancer by supporting the treatment options via the chemokine network in the tumor microenvironment.

Keywords

breast cancer
chemokines
tumor microenvironment
overall survivals
immune contexture

Author Information

Show +

Deok-Soo Son*
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Medicine, Meharry Medical College, Nashville, TN, USA
Samuel Evans Adunyah
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Medicine, Meharry Medical College, Nashville, TN, USA

*Address all correspondence to: dson@mmc.edu

1. Introduction

Chemokines are chemoattractant cytokines that recruit immune cells into the tumor microenvironment through interactions between chemokines and their specific receptors [1], building an immune context that affects cancer progression and prognosis. Chemokines consist of four groups based on the number of amino acids between the first cysteine (C) motifs as follows: C (XCL1-2), CC (CCL1-28), CXC (CXCL1-17), and CX3C (CX3CL1). Each chemokine recognizes the specific chemokine receptors (XCR1, CCR1-10, CXCR1-8, and CX3CR1) to control angiogenesis, regulate the immune network, and change cellular functions (Figure 1), creating the unique chemokine axis [1] as shown in Table 1.

Figure 1.
Chemokine signaling pathway. Modified and simplified from the KEGG PATHWAY Database (https://www.genome.jp/pathway/ko04062). The arrow (green) and block (gray) lines indicate positive and negative effects, respectively. PLC: phospholipase C; PKC: protein kinase C; PI3K: phosphoinositide 3-kinase; Akt: protein kinase B; GSK3: glycogen synthase kinase 3; BAD: BCL2 (B-cell leukemia/lymphoma 2) associated agonist of cell death; IKK: IkappaB kinase; IκB: inhibitor of nuclear factor kappa B; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; FOXO: forkhead box O; PKA: protein kinase A; SRC: proto-oncogene tyrosine-protein kinase Src; Shc: SHC adaptor protein; GRB2: growth factor receptor-bound protein 2; SOS: Son of sevenless; Ras: rat sarcoma virus; RAF: rapidly accelerated fibrosarcoma; MEK1: mitogen-activated protein kinase kinase 1; Erk1/2: extracellular signal-regulated kinase 1/2.

Receptors	Chemokines
XCR1	XCL1, 2
CCR1	CCL3, 5, 7, 8, 14, 15, 16, 23
CCR2	CCL2, 7, 8, 13, 16
CCR3	CCL5, 7, 11, 13, 14, 15, 24, 26, 28
CCR4	CCL17, 22
CCR5	CCL3, 4, 5, 8, 11, 14, 16
CCR6	CCL20
CCR7	CCL19, 21
CCR8	CCL1, 16
CCR9	CCL25
CCR10	CCL27, 28
CXCR1	CXCL6, 7, 8
CXCR2	CXCL1. 2, 3, 5, 6, 7, 8
CXCR3A	CXCL9, 10, 11
CXCR3B	CXCL4, 9, 10, 11
CXCR4	CXCL12
CXCR5	CXCL13
CXCR6	CXCL16
CXCR7	CXCL11, 12
CXCR8	CXCL17
CX3CR1	CX3CL1

Table 1.

Human chemokine network.

Orphan chemokines: CXCL14.

PITPNM3 is known as a receptor for CCL18.

A fifth molecular subtype of breast cancer is defined in large part by expression levels of hormone receptors, such as estrogen receptor (ER) and progesterone receptor (PR), and HER2 as follows: luminal A (ER+/PR+/HER2−), luminal B (ER+/PR+/HER2+), HER2-enriched (ER−/PR−/HER2+), basal-like, (triple-negative, ER−/PR−/HER2−), and normal breast-like (ER−/PR−/HER2−/CK5−/EGFR−). Chemokine signature in these subtypes was determined based on the expression module (PAM50 subtypes) provided by Breast Cancer Gene-Expression Miner v5.0 (bc-GenExMiner v5.0, http://bcgenex.ico.unicancer.fr/BC-GEM/GEM-Accueil.php?js=1) [2].

Chemokine signature between microarrays and RNA-seq shows a similar pattern except for CCL27 and CXCL4 expression levels (Figure 2). Generally, luminal subtypes have low expression levels of chemokines and chemokine receptors compared to other subtypes (Figure 2). In addition to chemokine signature in breast cancer subtypes, we have collected literature data on clinical aspects of chemokines in patients with breast cancer, excluding in vitro results of chemokines in breast cancer cell models and in vivo results of animal models for breast cancer. This chapter has described the functional roles of chemokine axes in breast cancer, focusing on chemokine signature in subtypes, overall survival, and clinicopathologic properties of chemokines in patients with breast cancer. Miner v5.0 (bc-GenExMiner v5.0, http://bcgenex.ico.unicancer.fr/BC-GEM/GEM-Accueil.php?js=1) was performed to determine the chemokine signature. Overall survivals in breast cancer were determined from a database provided by Kaplan-Meier Plotter (http://kmplot.com/analysis/index.php?p=background) [3].

Figure 2.
Chemokine signature in breast cancer subtypes. Heatmaps from a database of microarrays and RNA-seq. Breast Cancer Gene-Expression. LA: luminal A (n = 3946; 1343); LB: luminal B (n = 1889; 966); HER2: HER2-enriched (n = 1414; 693); BL: basal-like (n = 1976; 783); NBL: normal breast-like (n = 1079; 602).

2. The XCL1/2-XCR axis

Luminal B and HER2 subtypes show high levels of XCL1, XCL2, and XCR1 compared to luminal subtypes (Figure 2). XCL1 shows better survival in all breast cancers, BL/HER2/LB subtypes (Table 2), and ME−/MEL-TNBC (Table 3). XCL2 has better survival in all breast cancers and BL/HER2/LB subtypes (Table 2). XCR1 alone has no effects on survival except for good survival in MSL-TNBC (Table 3). Studies on the XCL1/2 in human breast cancer samples are lacking. The XCL1/2-XCR axis shows a benefit for breast cancer, which extends overall survival and reduces tumor growth.

Chemokines	ID	All		Basal-like		HER2		Luminal A		Luminal B		Normal
		HR	95% Cl	HR	95% Cl	HR	95% Cl	HR	95% Cl	HR	95% Cl	HR	95% Cl
XCL1	206365_at	0.75	0.62–0.91	0.44	0.29–0.66	0.63	0.43–0.93			0.66	0.46–0.94
XCL1	206366_x_at	0.75	0.62–0.91	0.44	0.29–0.66	0.63	0.43–0.93			0.66	0.46–0.94
XCL2	214567_s_at	0.77	0.64–0.93	0.37	0.24–0.55	0.58	0.39–0.86			0.61	0.43–0.88
CCL4	204103_at	0.73	0.61–0.89	0.58	0.39–0.86					0.66	0.46–0.95
CCL5	204655_at	0.82	0.68–0.99	0.30	0.20–0.47	0.67	0.46–0.99			0.65	0.45–0.92
CCL5	1405_i_at	0.82	0.68–0.99	0.30	0.20–0.47	0.67	0.46–0.99			0.65	0.45–0.92
CCL8	214038_at			0.61	0.41–0.90
CCL13	206407_s_at			0.66	0.45–0.96	0.63	0.43–0.93
CCL13	216714_at			0.66	0.45–0.96	0.63	0.43–0.93
CCL14	205392_s_at	0.74	0.61–0.89					0.94	0.62–1.44			2.78	0.96–8.07
CCL15	210390_s_at									1.51	1.06–2.14
CCL18	209924_at			0.58	0.39–0.86
CCL18	32128_at			0.58	0.39–0.86
CCL19	210072_at	0.73	0.60–0.88	0.59	0.40–0.87
CCL21	204606_at	0.76	0.63–0.92
CCL22	207861_at	0.74	0.61–0.89	0.55	0.37–0.81	0.57	0.38–0.84
CCL24	221463_at	1.21	1.00–1.46
CCL25	206988_at											2.48	1.12–10.8
CCL28	238750_at											0.23	0.05–1.11
CCL28	224240_s_at											0.23	0.05–1.11
CXCL8	202859_x_at	1.44	1.19–1.74
CXCL8	211506_s_at	1.44	1.19–1.74
CXCL9	203915_at	0.77	0.64–0.93	0.34	0.22–0.52	0.65	0.44–0.96			0.65	0.45–0.92
CXCL10	204533_at			0.43	0.28–0.64	0.68	0.46–1.01			0.62	0.43–0.88
CXCL11	211122_s_at			0.39	0.26–0.59
CXCL11	210163_at			0.39	0.26–0.59
CXCL12	203666_at	0.66	0.54–0.80
CXCL12	209687_at	0.66	0.54–0.80
CXCL13	205242_at	0.61	0.50–0.74	0.31	0.20–0.48	0.63	0.42–0.92			0.58	0.40–0.83
CXCL14	218002_s_at	0.71	0.59–0.86					0.59	0.38–0.91
CCR2	206978_at	0.74	0.61–0.89	0.57	0.38–0.84
CCR2	207794_at	0.74	0.61–0.89	0.57	0.38–0.84
CCR5	206991_s_at	0.68	0.56–0.82	0.46	0.31–0.70	0.52	0.35–0.78			0.49	0.34–0.70
CCR6	206983_at	0.69	0.57–0.84	0.64	0.43–0.94	0.60	0.40–0.89
CXCR2	207008_at					0.58	0.39–0.86
CXCR3	207681_at	0.74	0.61–0.90	0.55	0.37–0.81					0.59	0.41–0.85
CXCR3	217119_s_at	0.74	0.61–0.90	0.55	0.37–0.81					0.59	0.41–0.85
CXCR4	209201_x_at			0.48	0.32–0.71			1.62	1.05–2.50
	211919_s_at
	217028_at
CXCR6	206974_at	0.78	0.64–0.94	0.54	0.37–0.81	0.60	0.41–0.90			0.61	0.43–0.88
CXCR6	211469_s_at	0.78	0.64–0.94	0.54	0.37–0.81	0.60	0.41–0.90			0.61	0.43–0.88
CXCR7	212977_at	1.37	1.13–1.65			1.83	1.23–2.72
CXCR8	210264_at					1.67	1.12–2.49
CX3CR1	205898_at	0.61	0.50–0.74					0.63	0.41–0.98

Table 2.

Overall survivals based on expression levels of chemokines and chemokine receptors in breast cancer and its subtypes.

Bold HR: p < 0.05 increase or decrease. Chemokines and chemokine receptors without statistical significance on overall survival are not described. Sample No. by PAN50 subtype: All (n = 1879), BL (n = 431), HER2 (n = 431), LA (n = 596), LB (n = 439), and NBL (n = 51).

Chemokines	ID	BL1		BL2		IM		ME		MSL		LAR
		HR	95% Cl	HR	95% Cl	HR	95% Cl	HR	95% Cl	HR	95% Cl	HR	95% Cl
XCL1	206365_at							0.42	0.21–0.84	0.28	0.09–0.89
XCL1	206366_x_at							0.42	0.21–0.84	0.28	0.09–0.89
CCL14	205392_s_at											0.54	0.29–0.99
CCL19	210072_at									0.22	0.07–0.71
CCL22	207861_at	0.43	0.19–0.97							0.28	0.09–0.84	0.46	0.24–0.86
CCL25	21.7706988_at			3.48	1.17–10.3
CCL26	223710_at									3.68	1.13–12.0
CCL28	238750_at									0.31	0.10–0.96
CCL28	224240_s_at									0.31	0.10–0.96
CXCL2	209774_x_at			2.82	0.97–8.1
CXCL3	207850_at			3.86	1.24–12.0
CXCL0	206336_at									0.26	0.08–0.82
CXCL8	202859_x_at					2.83	1.18–6.80
CXCL8	211506_s_at					2.83	1.18–6.80
CXCL9	203915_at	0.38	0.17–0.88					0.37	0.18–0.76
CXCL10	204533_at							0.45	0.23–0.91
CXCL13	205242_at	0.30	0.13–0.72			0.34	0.14–0.82	0.41	0.21–0.80
XCR1	221468_at									0.21	0.06–0.76
CCR2	206978_at							0.45	0.23–0.89
CCR2	207794_at							0.45	0.23–0.89
CCR4	208376_at											0.50	0.26–0.93
	217970_s_at
	220671_at
CCR5	206991_s_at	0.40	0.17–0.92			0.29	0.12–0.73	0.48	0.24–0.97
CCR7	206337_at							0.34	0.17–0.70
CCR9	206887_at			3.13	1.01–9.71
CCR9	207445_s_at			3.13	1.01–9.71
CXCR3	207681_at	0.30	0.13–0.72
CXCR3	217119_s_at	0.30	0.13–0.72
CXCR6	206974_at					0.42	0.18–0.97
CXCR6	211469_s_at					0.42	0.18–0.97
CXCR8	210264_at											1.97	1.06–3.66
CX3CR1	205898_at					2.49	1.07–5.79

Table 3.

Overall survivals based on expression levels of chemokines and chemokine receptors in TNBC subtypes.

Bold HR: p < 0.05 increase or decrease. Chemokines and chemokine receptors without statistical significance on overall survival are not described. Sample No. by Pietenpol TNBC subtype: BL1 (n = 103), BL2 (n = 58), IM (n = 149), ME (n = 114), MSL (n = 39), LAR (n = 116).

3. The CCL-CCR axis

3.1 The CCL3/5/7/8/14/15/16/23-CCR1 axis

Although CCL3 is highly expressed in the BL subtype compared to other types (Figure 2), it has no effects on survival. CCL3 shows high levels in breast cancers, inflammatory BC, ER-negative, and PR-negative subtypes, of which expression levels are related to tumor grade, and show increased Ki67 (a proliferation marker). A good survival rate of CCL3 is reported, but non-TNBC has a poor survival rate [4, 5, 6, 7, 8, 9]. CCL5 is highly expressed in BL and HER2 subtypes compared to luminal subtypes (Figure 2) and shows better survival in all breast cancers and BL/HER2/LB subtypes (Table 2). CCL5 reduced the risks of breast cancer and LA/LB subtypes and had a good prognosis and survival, although poor survival in the HER2 subtype was reported [4, 5, 6, 7, 8]. CCL5 increased microvessel density and CD163+ Mφ infiltration [7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]. CCL7 is highly expressed in the BL subtype compared to other subtypes (Figure 2). CCL7 has no effects on survival from the database, although poor survival was reported [7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]. CCL7 is highly expressed in breast cancers, poorly differentiated cancers, TNBC, and African Americans. Expression levels of CCL7 are related to tumor grade and show the increased Ki67 [8, 12, 20]. CCL8 is highly expressed in BL and HER2 subtypes compared to other subtypes (Figure 2). CCL8 shows good survival in the BL subtype (Table 2) but is reported to have poor survival and prognosis, particularly in European Americans. CCL8 is highly expressed in ER-negative tumors, TNBC, and African Americans. Expression levels of CCL8 are related to tumor grade and show the increased Ki67 [8, 12, 21]. CCL14 is highly expressed in the NBL subtype compared to other subtypes (Figure 2). CCL14 has good survival in all breast cancers, the LA subtype, and LAR-TNBC, but shows poor survival in the NBL subtype (Tables 2 and 3). CCL14 is reported as an indicator of good survival and prognosis [10, 22]. CCL15 is similarly expressed between subtypes (Figure 2). CCL15 has poor survival in the LB subtype (Table 2) but is reported as an indicator of good survival and prognosis [6]. CCL16 is highly expressed in the NBL subtype compared to other subtypes (Figure 2). CCL16 has no effects on survivals from the database, although reports have shown an increased risk in the LA subtype and a decreased risk in TNBC [11]. CCL23 is highly expressed in the NBL subtype compared to other subtypes (Figure 2). Although CCL23 has no effects on survival, expression levels of CCL23 are related to tumor grade and good prognosis [8, 12]. CCR1 is highly expressed in the BL subtype compared to other subtypes (Figure 2) and has no effects on survival. Studies on CCR1 in patients with breast cancer are still lacking.

3.2 The CCL2/7/8/13/16-CCR2 axis

CCL2 is highly expressed in the BL subtype compared to luminal subtypes (Figure 2). CCL2 has no effects on survival from database, although it shows poor survival in both tumoral and stromal CCL2-positive cancers have the worse survival in the order of BL > HER2 > LB > LA subtypes. CCL2 is highly expressed in breast cancers, lower differentiated cells, invasive ductal ER-negative breast cancers, PR-negative breast cancers, cancer-associated fibroblasts, BL subtype, claudin-low cancers, and advanced cancers. Expression levels of CCL2 are related to early relapse, postmenopausal status, lymph node involvement, tumor grade, tumor size, and nodal status, showing induced angiogenesis and increased Ki67. CCL2 induced CD3, CD20, and CD68 infiltration with increased or unchanged tumor-associate macrophage (TAM) in tumors [5, 8, 20, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39]. CCL7, CCL8, and CCL16 are described in section of the CCL3/5/7/8/14/15/16/23-CCR1 axis. CCL13 is highly expressed in the BL subtype compared to other subtypes (Figure 2) and shows better survivals in BL and HER2 subtypes (Table 2). CCL13 is highly expressed in the HER2 subtype and shows the increased Ki67 [8]. CCR2 is highly expressed in BL/HER2/NBL subtypes compared to luminal subtypes (Figure 2). CCR2 has good survival in all breast cancers, BL subtype, and ME-TNBC (Tables 2 and 3). CCR2 is highly expressed in invasive ductal breast cancer and shows good survival [33, 40, 41].

3.3 The CCL5/7/11/13/14/15/24/26/28-CCR3 axis

CCL5, CCL7, CCL13, CCL14, and CCL15 are described in sections of the CCL3/5/7/8/14/15/16/23-CCR1 axis and the CCL2/7/8/13/16-CCR2 axis. CCL11 is highly expressed in the HER2 subtype compared to other subtypes (Figure 2) and has no effects on survival. CCL11 is highly expressed in the HER2 subtype and shows a good prognosis [12]. CCL24 is highly expressed in BL and NBL subtypes compared to other subtypes (Figure 2) and has poor survival in all breast cancers (Table 2), as shown in patients with breast cancer [6, 10]. CCL26 is highly expressed in BL and HER2 subtypes compared to other subtypes (Figure 2) and has poor survival in MSL-TNBC (Table 3). CCL26 is highly expressed in inflammatory breast cancers [4]. CCL28 is highly expressed in the NBL subtype compared to other types (Figure 2) and has good survivals in the NBL subtype and MSL-TNBC (Tables 2 and 3). CCR3 is highly expressed in the BL subtype compared to luminal subtypes based on RNA-seq, but it has generally low expression levels based on microarray (Figure 2). CCR3 has no effect on survival. Studies on CCR3 in patients with breast cancer are lacking.

3.4 The CCL17/22-CCR4 axis

CCL17 is highly expressed in BL/HER2/NBL subtypes compared to luminal subtypes (Figure 2). Although CCL17 has no effects on survival from the database, it shows a poor prognosis and survival in patients with breast cancer, particularly African Americans. CCL17 is highly expressed in TNBC and African Americans and is related to the induced Ki67 [6, 8, 12]. CCL22 is highly expressed in the HER2 subtype compared to other subtypes (Figure 2). CCL22 has good survival in all breast cancers, BL/HER2 subtypes, BL1-TNBC, MSL-TNBC, and LAR-TNBC (Tables 2 and 3). CCL22 is highly expressed in breast cancers and HER2 subtypes and is related to low grade, showing a good prognosis and unchanged or good survival [6, 10, 12, 20, 42]. CCR4 is highly expressed in BL and HER2 subtypes compared to luminal subtypes (Figure 2) and has a good survival in LAR-TNBC (Table 3). Expression levels of CCR4 are related to lymph node metastasis and HER2 expression [40, 43], and yet there are controversial survivals among patients with breast cancer.

3.5 The CCL3/4/5/8/11/14/16-CCR5 axis

CCL3, CCL5, CCL8, CCL11, CCL14, and CCL16 are described in sections of the CCR1/CCR2/CCR3 axis. CCL4 is highly expressed in the BL subtype compared to other types (Figure 2) and has good survival in all breast cancers and BL/LB subtypes (Table 2), as shown in patients with breast cancer. CCL4 is highly expressed in inflammatory breast cancers and ER-negative cancers and is related to metastasis of LB subtype and grade [4, 6, 8, 10, 12, 44]. CCR5 is highly expressed in BL and HER2 subtypes, as shown in patients with breast cancer, compared to luminal subtypes (Figure 2) [17]. CCR5 has good survival rates in all breast cancers, including BL/HER2/LB subtypes, BL1-TNBC, IM-TNBC, and ME-TNBC (Tables 2 and 3).

3.6 Orphan ligand CCL18

Although PITPNM3 is reported as a specific receptor for CCL18, further studies require clarifying the functional roles of chemokine receptors based on their similarity with CCR1-10. CCL18 is highly expressed in BL and HER2 subtypes compared to luminal subtypes (Figure 2) and shows good survival in the BL subtype (Table 2). CCL18 is highly expressed in breast cancers, advanced-stage cancers, and metastatic breast cancers and is related to metastasis and lymph node involvement. CCL18 shows a poor prognosis and survival in patients with breast cancer, particularly with higher CCL18-positive TAM [6, 20, 35, 45].

3.7 The CCL20-CCR6 axis

CCL20 is highly expressed in the BL subtype compared to other subtypes (Figure 2). Although CCL20 has no effects on survival from database, it shows poor survival in patients with breast cancer. CCL20 is highly expressed in TNBC, ER-negative cancers, and African Americans and is related to the induced Ki67 [8, 12, 46, 47]. CCR6 is highly expressed in LA and NBL subtypes compared to other subtypes (Figure 2) and has good survival in all breast cancers and BL/HER2 subtypes (Table 2). CCR6 is related to pleura metastasis and aggressive stage but has no effects on overall survival in patients with breast cancer [48, 49].

3.8 The CCL19/21-CCR7 axis

CCL19 is highly expressed in the NBL subtype compared to other subtypes (Figure 2) and shows better survival in all breast cancers, BL subtype, and MSL-TNBC (Tables 2 and 3). CCL19 is related to aggressive status and shows increased risks in the LA subtype but a good prognosis and survival in patients with breast cancer. Interestingly, patients with ER-positive cancers showed good survival with increased plasma levels of CCL19 but poor survival with tumoral levels of CCL19 [6, 10, 11, 12, 40, 49]. CCL21 is highly expressed in the NBL subtype compared to other subtypes (Figure 2) and shows better survival in all breast cancers (Table 2). CCL21 is highly expressed in metastatic breast cancers and has a good prognosis and survival [6, 10, 12, 22, 40, 50]. CCR7 is highly expressed in BL/HER2/NBL subtypes compared to luminal subtypes (Figure 2) and has good survival in ME-TNBC (Table 3). CCR7 is highly expressed in breast cancers, metastatic breast cancers, HER2 subtype, LB subtype, and TNBC and is related to lymph node metastasis in part, recurrence in part, TNM stage, grade, invasion, and aggressive status. CCR7 induced CD68 and FOXP3 cell infiltration but had no change in CD8 and CD20 cell infiltration. There are controversial survivals, including good, no change, and poor survivals, among patients with breast cancer [48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60].

3.9 The CCL1/16-CCR8 axis

CCL1 is highly expressed in the BL subtype compared to other subtypes (Figure 2) and has no effects on survival. CCL1 is highly expressed in invasive cancers and ER-negative cancers and is related to tumor grade. CCL1 increased Treg infiltration and showed poor survival in patients with breast cancer [35, 42]. CCL16 is described in the section of the CCL3/5/7/8/14/15/16/23-CCR1 axis. CCR8 is highly expressed in BL and HER2 subtypes compared to luminal subtypes (Figure 2) and has no effects on survival. Studies on CCR8 in patients with breast cancer are lacking.

3.10 The CCL25-CCR9 axis

CCL25 is highly expressed in the BL subtype compared to other subtypes (Figure 2) and has poor survival in the NBL subtype and BL2-TNBC (Tables 2 and 3). CCL25 is highly expressed in TNBC in African Americans, and it shows poor survival, particularly in African Americans [12]. CCR9 is highly expressed in BL and NBL subtypes compared to other subtypes (Figure 2) and has poor survival in BL2-TNBC (Table 3). CCR9 is highly expressed in poorly differentiated breast cancers [61].

3.11 The CCL27/28-CCR10 axis

CCL28 is described in section of the CCL5/7/11/13/14/15/24/26/28-CCR3 axis. CCL27 is highly expressed in all breast cancer subtypes based on RNA-seq, but it generally has low expression levels based on microarray (Figure 2). CCL27 has no effect on survival. CCL27 is highly expressed in inflammatory breast cancers [4]. CCR10 is highly expressed in NBL subtypes compared to other subtypes (Figure 2) and has no effects on survival. Studies on CCR10 in patients with breast cancer are lacking.

4. The CXCL-CXCR axis

4.1 The CXCL6/7/8-CXCR1 axis

CXCL6 is highly expressed in BL/NBL subtypes compared to other subtypes (Figure 2) and has a good survival in MSL-TNBC (Table 3). CXCL6 is highly expressed in ER-negative breast cancers and is related to metastasis of breast cancers, showing unchanging or good survival [62, 63]. CXCL7 is highly expressed in BL/NBL subtypes compared to other subtypes (Figure 2) and has no effects on survival. CXCL7 is related to stage III breast cancers and has controversial survivals: good, unchanging, and poor [10, 62, 64, 65, 66]. CXCL8 is highly expressed in BL/HER2 subtypes compared to other subtypes (Figure 2) and has poor survival in all breast cancers and IM-TNBC (Tables 2 and 3). In human breast cancer samples, CXCL8 is highly expressed in breast cancers, inflammatory breast cancers, TNBC, advanced stage cancers, HER2/LA/LB subtypes, ER and PR-negative breast cancers, and cancer-associated fibroblasts (CAFs), and is related to metastasis of breast cancers and lymph nodes and tumor grade and stage, showing induced angiogenesis and increased Ki67. CXCL8 induced CD68 infiltration and had a poor prognosis and survival, particularly in patients with CXCL8 (−251) A allele [4, 5, 8, 10, 20, 29, 44, 62, 63, 64, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76]. CXCR1 is a little bit highly expressed in HER2 and NBL subtypes compared to other subtypes (Figure 2) and has no effects on survival. CXCR1 is highly expressed in invasive breast cancers [41].

4.2 The CXCL1/2/3/5/6/7/8-CXCR2 axis

CXCL1 is highly expressed in the BL subtype compared to other subtypes (Figure 2) and has no effects on survivals. CXCL1 is highly expressed in breast cancers, TNBC, and ER-negative cancers and is related to metastasis of breast cancer and grade with increased Ki67. CXCL1 increased CD133 (stem cell marker) and CD68 (Mφ marker) cell infiltration and shows a poor prognosis and controversial survivals: poor, unchanging, and good [8, 63, 77, 78, 79, 80, 81]. CXCL2 is highly expressed in the NBL subtype compared to other subtypes (Figure 2) and has poor survival in BL2-TNBC (Table 3). CXCL2 is related to metastasis of breast cancer and shows a good prognosis and survival [62, 63, 65, 80]. CXCL3 is highly expressed in BL and NBL subtypes compared to other subtypes (Figure 2) and has poor survival in BL2-TNBC (Table 3). CXCL3 is highly expressed in aggressive breast cancers and is related to metastasis of breast cancer. CXCL3 shows a poor prognosis and controversial survivals: poor, unchanged, and good [62, 63, 64, 65, 80, 82]. CXCL5 is highly expressed in the BL subtype compared to other subtypes (Figure 2) and has no effects on survivals. CXCL5 is highly expressed in breast cancers and ER-negative cancers and is related to low metastasis in the LB subtype. CXCL5 has no effects on survival [8, 23, 35, 44, 63]. CXCL6, CXCL7, and CXCL8 are described in a section of the CXCL6/7/8-CXCR1 axis. CXCR2 is highly expressed in BL and NBL subtypes compared to other subtypes (Figure 2) and has a good survival in the HER2 subtype (Table 2). CXCR2 is highly expressed in high-grade breast cancers, TNBC, ER and PR-negative breast cancers, and invasive breast cancers but shows low levels in relapse cases. CXCR2 enhanced tumoral TILs, CD3, CD8, PD-L1, and T/B-cell infiltration and showed good or poor survival in patients with breast cancers. Interestingly, CXCR2 C1208T variation increased the risk of breast cancer, leading to poor survival [41, 76, 83, 84, 85, 86].

4.3 The CXCL4/9/10/11-CXCR3 axis

CXCL4 is highly expressed in all breast cancer subtypes based on RNA-seq compared to microarray (Figure 2). CXCL4 has no effect on survival. Studies on CXCL4 in human breast cancer samples are lacking. CXCL9 is highly expressed in BL and HER2 subtypes compared to other subtypes (Figure 2) and has a good survival in all breast cancers, BL/HER2/LB subtypes, and BL1−/ME-TNBC (Tables 2 and 3). CXCL9 is highly expressed in breast cancers, TNBC, low-proliferative cells, lymph node-negative breast cancers, HER2 subtype, and ER-negative cancers and is related to tumor grade with increased Ki67. CXCL9 has a good prognosis and both good and poor survivals, particularly showing good survivals in TNBC and luminal HER2 breast cancers [8, 10, 20, 22, 62, 64, 65, 80, 87]. CXCL10 is highly expressed in BL and HER2 subtypes compared to other subtypes (Figure 2) and has a good survival in BL/HER2/LB subtypes and ME-TNBC (Tables 2 and 3). CXCL10 is highly expressed in breast cancers, poorly differentiated tumors, HER2 subtype, HR- and ER-negative cancers and is related to tumor grade and stage with increased Ki67 positive cells and TIL infiltration. CXCL10 has a good prognosis but no change in survival [8, 20, 62, 65, 80, 88, 89, 90]. CXCL11 is highly expressed in BL and HER2 subtypes compared to other subtypes (Figure 2) and has a good survival in the BL subtype (Table 2). CXCL11 is highly expressed in breast cancers, TNBC, HER2 subtype, and ER-negative cancers and is related to tumor grade with increased Ki67 positive cells, showing no change in survivals [8, 20, 80]. CXCR3 is highly expressed in BL and HER2 subtypes compared to other subtypes (Figure 2) and has a good survival in all breast cancers, BL/LB subtypes, and BL1-TNBC (Tables 2 and 3). CXCR3 is highly expressed in ER-negative breast cancers and is related to tumor grade and size. CXCR3 shows both good and poor survivals in breast cancers, particularly good survivals in BL subtype, ER-negative cancers, and LN-positive cancers [91, 92, 93, 94].

4.4 The CXCL12-CXCR4 axis

CXCL12 is highly expressed in the NBL subtype compared to other subtypes (Figure 2) and has a good survival in all breast cancers (Table 2). CXCL12 is highly expressed in breast cancers and BL subtypes and is related to tumor stage, tumor grade, and lymph node metastasis with increased Treg infiltration. CXCL12 has a good prognosis and survival in patients with breast cancers [62, 64, 95], particularly in patients with high plasma levels of CXCL12 and CXCL12δ isoforms. Some studies show no change in CXCL12 levels between subtypes and survivals [10, 22, 35, 62, 64, 65, 80, 95, 96, 97, 98, 99, 100, 101, 102]. CXCR4 is highly expressed in BL and HER2 subtypes compared to other subtypes (Figure 2) and has good survival in the BL subtype but poor survival in the LA subtype (Table 2). CXCR4 is highly expressed in breast cancers, BL/HER2/LA/LB subtypes, locally advanced breast cancers, TNBC, ER and PR-negative cancers, atypical ductal hyperplasia, ductal carcinoma in situ, and invasive breast cancers. CXCR4 is related to the metastasis of TNBC, liver metastasis, lymph node metastasis, distant metastasis, recurrence in HER2 negative cancers and TNBC, tumor grade, and tumor size, and advanced TNM stage in TNBC, showing increased CXCR4 positive Treg infiltration in BL subtype compared to luminal subtypes. CXCR4 has controversial survivals for breast cancers as follows: good survivals, particularly in highly expressed CXCR4 fibroblasts, BL subtype, and ER-negative cancers; unchanged survivals; poor survivals, particularly in TNBC and patients with unmethylated CXCR4 or hypermethylated CXCL12/unmethylated CXCR4 [41, 48, 51, 54, 55, 59, 91, 92, 95, 96, 97, 98, 100, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125].

4.5 The CXCL13-CXCR5 axis

CXCL13 is highly expressed in BL and HER2 subtypes compared to other subtypes (Figure 2) and has a good survival in all breast cancers, BL/HER2/LB subtypes, and BL1−/IM−/ME-TNBCs (Tables 2 and 3). CXCL13 is highly expressed in breast cancers, ER-negative cancers, and metastatic breast cancers and is related to lymph node metastasis with CXCR5 co-expression and increased Ki67. CXCL13 has a good prognosis and both unchanged and good survival in patients with breast cancers [10, 22, 35, 62, 64, 65, 80, 87, 126, 127]. CXCR5 is highly expressed in BL/HER2/NBL subtypes compared to luminal subtypes (Figure 2) and does not affect survival. CXCR5 is related to lymph node metastasis and tumor stage [75].

4.6 Orphan ligand CXCL14

CXCL14 is highly expressed in LA and NBL subtypes compared to other subtypes (Figure 2) and has a good survival in all breast cancers and LA subtypes (Table 2). CXCL14 is related to lymph node metastasis and has good survival in all breast cancers and BL/HER2/LA subtypes [10, 62, 64, 128, 129].

4.7 The CXCL16-CXCR6 axis

CXCL16 is highly expressed in the BL subtype compared to other subtypes (Figure 2) and has no change in survivals. CXCL16 increased the risk of cancer in the HER2 subtype [11]. CXCR6 is highly expressed in BL and HER2 subtypes compared to other subtypes (Figure 2) and has good survival in all breast cancers, BL/HER2/LB subtypes, and IM-TNBC (Tables 2 and 3). Studies on CXCR6 in human breast cancer samples are lacking.

4.8 The CXCL11/12-CXCR7 (ACKR3) axis

CXCL11 and CXCL12 are described in sections of the CXCL4/9/10/11-CXCR3 axis and the CXCL12-CXCR4 axis. CXCR7 is lowly expressed in the BL subtype compared to other subtypes (Figure 2) and has poor survival in all breast cancers and HER2 subtypes (Table 2). CXCR7 is highly expressed in TNBC, ER/PR-negative, or positive cancers and is related to TNM stage and tumor grade, showing poor survival [97, 130, 131].

4.9 The CXCL17-CXCR8 (GPR35) axis

CXCL17 is highly expressed in the HER2 subtype compared to other subtypes (Figure 2) and has no change in survivals. Studies on CXCL17 in human breast cancer samples are lacking. CXCR8 is highly expressed in LA and NBL subtypes compared to other subtypes (Figure 2) and has poor survivals in the HER2 subtype and LAR-TNBC (Tables 2 and 3). Studies on CXCR8 in human breast cancer samples are lacking.

5. The CX3CL1-CX3CR1 axis

CX3CL1 is highly expressed in BL and NBL subtypes compared to other subtypes (Figure 2) and has no change in survivals. CX3CL1 is highly expressed in inflammatory breast cancers, LB subtype, and PR-positive cancers and is related to tumor grade, tumor stage, tumor size, and lymph node metastasis with increased Ki67, stromal CD8, intratumoral DC, stromal NK, and TIL infiltration, showing both good and poor survivals [4, 8, 132, 133]. CX3CR1 is highly expressed in LA and NBL subtypes compared to other subtypes (Figure 2) and has good survival in all breast cancers and LA subtypes but poor survival in IM-TNBC (Tables 2 and 3). CX3CR1 is related to brain metastasis but has no change in survival [48].

6. Summary/conclusion

Chemokine axes are likely to prefer cell migration and invasion rather than cell proliferation, leading to changed immune contexture in the tumor microenvironment followed by altered overall survivals. Accordingly, chemokines are likely to play a critical role in cancer cell metastasis and immune cell contexture, contributing to tumor size, grade, and stage. Some chemokines are related to tumor growth and angiogenesis through increased viability and angiogenic genes. Also, some chemokines are involved in cancer recurrence and chemoresistance, diminishing therapeutic effectiveness. Based on data obtained from human breast cancer samples, overall survivals are summarized by the chemokines-chemokine receptor axis (Figure 3). The XCL-XCR axis shows good survival. The CCL-CCR axis indicates various survivals as follows: good survivals in CC4, CCL5, CCL13, CCL14, CCL19, CCL21, CCL22, CCR5, and CCR6; poor survivals in CCL24 and CCL25; controversial survivals in CCL1, CCL2, CCL8, CCL15, CCL17, CCL20, CCR2, CCR4, CCR7, and CCR9; unchanged survivals in CCL3, CCL7, CCL11, CCL16, CCL23, CCL26, CCL27, CCL28, CCR1, CCR3, CCR8, and CCR10. The CXCL-CXCR axis also indicates various survivals as follows: good survivals in CXCL6, CXCL12, CXCL13, CXCR3, and CXCR6; poor survivals in CXCL8, CXCR7, and CXCR8; controversial survivals in CXCL1, CXCL2, CXCL3, CXCL7, CXCL9, CXCR2, and CXCR4; unchanged survivals in CXCL4, CXCL5, CXCL10, CXCL11, CXCL16, CXCL17, CXCR1, and CXCR5. Orphan chemokines CCL18 and CXCL14 have controversial and good survivals, respectively. The CX3CL1-CX3CR1 axis shows controversial survivals (Figure 3). There are differential chemokine signatures between tumor cells, stromal cells, immune cells, and adipocytes in the breast tumor microenvironment. Therefore, cell-to-cell communication via the chemokine network is complex in the breast tumor microenvironment, which cannot be simply explained with one chemokine. Although CCL2, CXCL12, and CXCR4 have been studied extensively, there are still many chemokines that require clarification of their roles in breast cancers.

Figure 3.
Impacts of chemokine axis on overall survivals in breast cancers. Green: good survivals; pink: poor survivals; yellow: controversial survivals; gray: unchanged survivals.

In conclusion, chemokines play a critical role in breast cancer progression, changing the breast tumor microenvironment through immune cell infiltration, cell-to-cell crosstalk, metastasis, chemoresistance, and tumor growth, followed by altered prognosis and survival.

Acknowledgments

This work was supported, in whole or in part, by research funds from the National Institutes of Health (NIH) and the American Cancer Society (ACS) as follows: U54MD007586, U54CA163069, and ACS DICRIDG-21-071-01-DICRIDG.

References

1. Masih M, Agarwal S, Kaur R, Gautam PK. Role of chemokines in breast cancer. Cytokine. 2022;155:155909
2. Jézéquel P, Gouraud W, Ben Azzouz F, Guérin-Charbonnel C, Juin PP, Lasla H, et al. Bc-GenExMiner 4.5: New mining module computes breast cancer differential gene expression analyses. Database: The Journal of Biological Databases and Curation. 2021;2021:baab007
3. Győrffy B. Survival analysis across the entire transcriptome identifies biomarkers with the highest prognostic power in breast cancer. Computational and Structural Biotechnology Journal. 2021;19:4101-4109
4. Bessaad M, Habel A, Hadj Ahmed M, Xu W, Stayoussef M, Bouaziz H, et al. Assessing serum cytokine profiles in inflammatory breast cancer patients using Luminex® technology. Cytokine. 2023;172:156409
5. Chavey C, Bibeau F, Gourgou-Bourgade S, Burlinchon S, Boissière F, Laune D, et al. Oestrogen receptor negative breast cancers exhibit high cytokine content. Breast Cancer Research. 2007;9:R15
6. Chen B, Zhang S, Li Q , Wu S, He H, Huang J. Bioinformatics identification of CCL8/21 as potential prognostic biomarkers in breast cancer microenvironment. Bioscience Reports. 2020;40:BSR20202042
7. Bièche I, Lerebours F, Tozlu S, Espie M, Marty M, Lidereau R. Molecular profiling of inflammatory breast cancer: Identification of a poor-prognosis gene expression signature. Clinical Cancer Research. 2004;10:6789-6795
8. Franzén B, Alexeyenko A, Kamali-Moghaddam M, Hatschek T, Kanter L, Ramqvist T, et al. Protein profiling of fine-needle aspirates reveals subtype-associated immune signatures and involvement of chemokines in breast cancer. Molecular Oncology. 2019;13:376-391
9. Farmaki E, Kaza V, Papavassiliou AG, Chatzistamou I, Kiaris H. Induction of the MCP chemokine cluster cascade in the periphery by cancer cell-derived Ccl3. Cancer Letters. 2017;389:49-58
10. Hozhabri H, Moghaddam MM, Moghaddam MM, Mohammadian A. A comprehensive bioinformatics analysis to identify potential prognostic biomarkers among CC and CXC chemokines in breast cancer. Scientific Reports. 2022;12:10374
11. Yu X, Zhang Y, Lin Y, Zou S, Zhu P, Song M, et al. The association between plasma chemokines and breast cancer risk and prognosis: A mendelian randomization study. Frontiers in Genetics. 2022;13:1004931
12. Thomas JK, Mir H, Kapur N, Bae S, Singh S. CC chemokines are differentially expressed in breast cancer and are associated with disparity in overall survival. Scientific Reports. 2019;9:4014
13. Yamaguchi M, Takagi K, Narita K, Miki Y, Onodera Y, Miyashita M, et al. Stromal CCL5 promotes breast cancer progression by interacting with CCR3 in tumor cells. International Journal of Molecular Sciences. 2021;22:1918
14. Zazo S, González-Alonso P, Martín-Aparicio E, Chamizo C, Luque M, Sanz-Álvarez M, et al. Autocrine CCL5 effect mediates trastuzumab resistance by ERK pathway activation in HER2-positive breast cancer. Molecular Cancer Therapeutics. 2020;19:1696-1707
15. Luboshits G, Shina S, Kaplan O, Engelberg S, Nass D, Lifshitz-Mercer B, et al. Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma. Cancer Research. 1999;59:4681-4687
16. Zhang Y, Yao F, Yao X, Yi C, Tan C, Wei L, et al. Role of CCL5 in invasion, proliferation and proportion of CD44+/CD24- phenotype of MCF-7 cells and correlation of CCL5 and CCR5 expression with breast cancer progression. Oncology Reports. 2009;21:1113-1121
17. Velasco-Velázquez M, Jiao X, De La Fuente M, Pestell TG, Ertel A, Lisanti MP, et al. CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Research. 2012;72:3839-3850
18. Zhang Q , Qin J, Zhong L, Gong L, Zhang B, Zhang Y, et al. CCL5-mediated Th2 immune polarization promotes metastasis in luminal breast cancer. Cancer Research. 2015;75:4312-4321
19. Derossi DR, Amarante MK, Guembarovski RL, de Oliveira CEC, Suzuki KM, Watanabe MAE, et al. CCL5 protein level: Influence on breast cancer staging and lymph nodes commitment. Molecular Biology Reports. 2019;46:6165-6170
20. Narita D, Seclaman E, Anghel A, Ilina R, Cireap N, Negru S, et al. Altered levels of plasma chemokines in breast cancer and their association with clinical and pathological characteristics. Neoplasma. 2016;63:141-149
21. Farmaki E, Chatzistamou I, Kaza V, Kiaris H. A CCL8 gradient drives breast cancer cell dissemination. Oncogene. 2016;35:6309-6318
22. Mehraj U, Alshehri B, Khan AA, Bhat AA, Bagga P, Wani NA, et al. Expression pattern and prognostic significance of chemokines in breast cancer: An integrated bioinformatics analysis. Clinical Breast Cancer. 2022;22:567-578
23. Li X, Wang M, Gong T, Lei X, Hu T, Tian M, et al. A S100A14-CCL2/CXCL5 signaling axis drives breast cancer metastasis. Theranostics. 2020;10:5687-5703
24. Valković T, Lucin K, Krstulja M, Dobi-Babić R, Jonjić N. Expression of monocyte chemotactic protein-1 in human invasive ductal breast cancer. Pathology, Research and Practice. 1998;194:335-340
25. Ueno T, Toi M, Saji H, Muta M, Bando H, Kuroi K, et al. Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clinical Cancer Research. 2000;6:3282-3289
26. Saji H, Koike M, Yamori T, Saji S, Seiki M, Matsushima K, et al. Significant correlation of monocyte chemoattractant protein-1 expression with neovascularization and progression of breast carcinoma. Cancer. 2001;92:1085-1091
27. Valković T, Fuckar D, Stifter S, Matusan K, Hasan M, Dobrila F, et al. Macrophage level is not affected by monocyte chemotactic protein-1 in invasive ductal breast carcinoma. Journal of Cancer Research and Clinical Oncology. 2005;131:453-458
28. Fujimoto H, Sangai T, Ishii G, Ikehara A, Nagashima T, Miyazaki M, et al. Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. International Journal of Cancer. 2009;125:1276-1284
29. Katanov C, Lerrer S, Liubomirski Y, Leider-Trejo L, Meshel T, Bar J, et al. Regulation of the inflammatory profile of stromal cells in human breast cancer: Prominent roles for TNF-α and the NF-κB pathway. Stem Cell Research & Therapy. 2015;6:87
30. Li D, Ji H, Niu X, Yin L, Wang Y, Gu Y, et al. Tumor-associated macrophages secrete CC-chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer. Cancer Science. 2020;111:47-58
31. Dwyer RM, Potter-Beirne SM, Harrington KA, Lowery AJ, Hennessy E, Murphy JM, et al. Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clinical Cancer Research. 2007;13:5020-5027
32. Dutta P, Sarkissyan M, Paico K, Wu Y, Vadgama JV. MCP-1 is overexpressed in triple-negative breast cancers and drives cancer invasiveness and metastasis. Breast Cancer Research and Treatment. 2018;170:477-486
33. Fang WB, Sofia Acevedo D, Smart C, Zinda B, Alissa N, Warren K, et al. Expression of CCL2/CCR2 signaling proteins in breast carcinoma cells is associated with invasive progression. Scientific Reports. 2021;11:8708
34. Fang WB, Yao M, Jokar I, Alhakamy N, Berkland C, Chen J, et al. The CCL2 chemokine is a negative regulator of autophagy and necrosis in luminal B breast cancer cells. Breast Cancer Research and Treatment. 2015;150:309-320
35. Cui K, Song N, Fan Y, Zeng L, Shi P, Wang Z, et al. A two-sample Mendelian randomization analysis: Causal association between chemokines and pan-carcinoma. Frontiers in Genetics. 2023;14:1285274
36. Lebrecht A, Grimm C, Lantzsch T, Ludwig E, Hefler L, Ulbrich E, et al. Monocyte chemoattractant protein-1 serum levels in patients with breast cancer. Tumour Biology. 2004;25:14-17
37. Wang J, Zhuang ZG, Xu SF, He Q , Shao YG, Ji M, et al. Expression of CCL2 is significantly different in five breast cancer genotypes and predicts patient outcome. International Journal of Clinical and Experimental Medicine. 2015;8:15684-15691
38. Heiskala M, Leidenius M, Joensuu K, Heikkilä P. High expression of CCL2 in tumor cells and abundant infiltration with CD14 positive macrophages predict early relapse in breast cancer. Virchows Archiv. 2019;474:3-12
39. Lubowicka E, Przylipiak A, Zajkowska M, Piskór BM, Malinowski P, Fiedorowicz W, et al. Plasma chemokine CCL2 and its receptor CCR2 concentrations as diagnostic biomarkers for breast cancer patients. BioMed Research International. 2018;2018:2124390
40. Xu M, Li Y, Li W, Zhao Q , Zhang Q , Le K, et al. Immune and stroma related genes in breast cancer: A comprehensive analysis of tumor microenvironment based on the cancer genome atlas (TCGA) database. Frontiers in Medicine (Lausanne). 2020;7:64
41. Seo EH, Namgung JH, Oh CS, Kim SH, Lee SH. Association of Chemokines and Chemokine Receptor Expression with Monocytic-myeloid-derived suppressor cells during tumor progression. Immune Network. 2018;18:e23
42. Kuehnemuth B, Piseddu I, Wiedemann GM, Lauseker M, Kuhn C, Hofmann S, et al. CCL1 is a major regulatory T cell attracting factor in human breast cancer. BMC Cancer. 2018;18:1278
43. Li JY, Ou ZL, Yu SJ, Gu XL, Yang C, Chen AX, et al. The chemokine receptor CCR4 promotes tumor growth and lung metastasis in breast cancer. Breast Cancer Research and Treatment. 2012;131:837-848
44. de Araújo RA, da Luz FAC, da Costa ME, Nascimento CP, Mendes TR, Mosca ERT, et al. The elusive luminal B breast cancer and the mysterious chemokines. Journal of Cancer Research and Clinical Oncology. 2023;149:12807-12819
45. Chen J, Yao Y, Gong C, Yu F, Su S, Chen J, et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. 2011;19:541-555
46. Lee SK, Park KK, Kim HJ, Park J, Son SH, Kim KR, et al. Human antigen R-regulated CCL20 contributes to osteolytic breast cancer bone metastasis. Scientific Reports. 2017;7:9610
47. Chen W, Qin Y, Wang D, Zhou L, Liu Y, Chen S, et al. CCL20 triggered by chemotherapy hinders the therapeutic efficacy of breast cancer. PLoS Biology. 2018;16:e2005869
48. Andre F, Cabioglu N, Assi H, Sabourin JC, Delaloge S, Sahin A, et al. Expression of chemokine receptors predicts the site of metastatic relapse in patients with axillary node positive primary breast cancer. Annals of Oncology. 2006;17:945-951
49. Cassier PA, Treilleux I, Bachelot T, Ray-Coquard I, Bendriss-Vermare N, Ménétrier-Caux C, et al. Prognostic value of the expression of C-chemokine receptor 6 and 7 and their ligands in non-metastatic breast cancer. BMC Cancer. 2011;11:213
50. Mohammed MM, Shaker O, Ramzy MM, Gaber SS, Kamel HS, Abed El Baky MF. The relation between ACKR4 and CCR7 genes expression and breast cancer metastasis. Life Sciences. 2021;279:119691
51. Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50-56
52. Li F, Zou Z, Suo N, Zhang Z, Wan F, Zhong G, et al. CCL21/CCR7 axis activating chemotaxis accompanied with epithelial-mesenchymal transition in human breast carcinoma. Medical Oncology. 2014;31:180
53. Gurgel DC, Wong DVT, Bandeira AM, Pereira JFB, Gomes-Filho JV, Pereira AC, et al. Cytoplasmic CCR7 (CCR7c) immunoexpression is associated with local tumor recurrence in triple-negative breast cancer. Pathology, Research and Practice. 2020;216:153265
54. Liu Y, Ji R, Li J, Gu Q , Zhao X, Sun T, et al. Correlation effect of EGFR and CXCR4 and CCR7 chemokine receptors in predicting breast cancer metastasis and prognosis. Journal of Experimental & Clinical Cancer Research. 2010;29:16
55. Cabioglu N, Yazici MS, Arun B, Broglio KR, Hortobagyi GN, Price JE, et al. CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer. Clinical Cancer Research. 2005;11:5686-5693
56. Sonbul SN, Gorringe KL, Aleskandarany MA, Mukherjee A, Green AR, Ellis IO, et al. Chemokine (C-C motif) receptor 7 (CCR7) associates with the tumour immune microenvironment but not progression in invasive breast carcinoma. The Journal of Pathology. Clinical Research. 2017;3:105-114
57. Wu J, Li L, Liu J, Wang Y, Wang Z, Wang Y, et al. CC chemokine receptor 7 promotes triple-negative breast cancer growth and metastasis. Acta Biochimica et Biophysica Sinica (Shanghai). 2018;50:835-842
58. Li X, Sun S, Li N, Gao J, Yu J, Zhao J, et al. High expression of CCR7 predicts lymph node metastasis and good prognosis in triple negative breast cancer. Cellular Physiology and Biochemistry. 2017;43:531-539
59. Strien L, Joensuu K, Heikkilä P, Leidenius MH. Different expression patterns of CXCR4, CCR7, Maspin and FOXP3 in luminal breast cancers and their sentinel node metastases. Anticancer Research. 2017;37:175-182
60. Vahedi L, Ghasemi M, Yazdani J, Ranjbar S, Nouri B, Alizadeh A, et al. Investigation of CCR7 marker expression using immunohistochemical method and its association with clinicopathologic properties in patients with breast cancer. International Journal of Hematology-Oncology and Stem Cell Research. 2018;12:103-110
61. Johnson-Holiday C, Singh R, Johnson E, Singh S, Stockard CR, Grizzle WE, et al. CCL25 mediates migration, invasion and matrix metalloproteinase expression by breast cancer cells in a CCR9-dependent fashion. International Journal of Oncology. 2011;38:1279-1285
62. Li L, Yao W, Yan S, Dong X, Lv Z, Jing Q , et al. Pan-cancer analysis of prognostic and immune infiltrates for CXCs. Cancers (Basel). 2021;13:4153
63. Bièche I, Chavey C, Andrieu C, Busson M, Vacher S, Le Corre L, et al. CXC chemokines located in the 4q21 region are up-regulated in breast cancer. Endocrine-Related Cancer. 2007;14:1039-1052
64. Chen E, Qin X, Peng K, Xu X, Li W, Cheng X, et al. Identification of potential therapeutic targets among CXC chemokines in breast tumor microenvironment using integrative bioinformatics analysis. Cellular Physiology and Biochemistry. 2018;45:1731-1746
65. Li Y, Liang M, Lin Y, Lv J, Chen M, Zhou P, et al. Transcriptional expressions of CXCL9/10/12/13 as prognosis factors in breast cancer. Journal of Oncology. 2020;2020:4270957
66. Wang YH, Shen CY, Lin SC, Kuo WH, Kuo YT, Hsu YL, et al. Monocytes secrete CXCL7 to promote breast cancer progression. Cell Death & Disease. 2021;12:1090
67. Motyka J, Gacuta E, Kicman A, Kulesza M, Ławicki P, Ławicki S. Plasma levels of CXC motif chemokine 1 (CXCL1) and chemokine 8 (CXCL8) as diagnostic biomarkers in luminal A and B breast cancer. Journal of Clinical Medicine. 2022;11:6694
68. Fang QI, Wang X, Luo G, Yu M, Zhang X, Xu N. Increased CXCL8 expression is negatively correlated with the overall survival of patients with ER-negative breast cancer. Anticancer Research. 2017;37:4845-4852
69. Milovanovic J, Todorovic-Rakovic N, Abu RZ. The prognostic role of interleukin-8 (IL-8) and matrix metalloproteinases −2 and −9 in lymph node-negative untreated breast cancer patients. JBUON. 2013;18:866-873
70. Benoy IH, Salgado R, Van Dam P, Geboers K, Van Marck E, Scharpé S, et al. Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival. Clinical Cancer Research. 2004;10:7157-7162
71. Ma Y, Ren Y, Dai ZJ, Wu CJ, Ji YH, Xu J. IL-6, IL-8 and TNF-α levels correlate with disease stage in breast cancer patients. Advances in Clinical and Experimental Medicine. 2017;26:421-426
72. Celik B, Yalcin AD, Genc GE, Bulut T, Kuloglu Genc S, Gumuslu S. CXCL8, IL-1β and sCD200 are pro-inflammatory cytokines and their levels increase in the circulation of breast carcinoma patients. Biomedical Report. 2016;5:259-263
73. Tiainen L, Hämäläinen M, Luukkaala T, Tanner M, Lahdenperä O, Vihinen P, et al. Low plasma IL-8 levels during chemotherapy are predictive of excellent long-term survival in metastatic breast cancer. Clinical Breast Cancer. 2019;19:e522-e533
74. König A, Vilsmaier T, Rack B, Friese K, Janni W, Jeschke U, et al. Determination of Interleukin-4, −5, −6, −8 and −13 in serum of patients with breast cancer before treatment and its correlation to circulating tumor cells. Anticancer Research. 2016;36:3123-3130
75. Razmkhah M, Jaberipour M, Safaei A, Talei AR, Erfani N, Ghaderi A. Chemokine and chemokine receptors: A comparative study between metastatic and nonmetastatic lymph nodes in breast cancer patients. European Cytokine Network. 2012;23:72-77
76. Snoussi K, Mahfoudh W, Bouaouina N, Fekih M, Khairi H, Helal AN, et al. Combined effects of IL-8 and CXCR2 gene polymorphisms on breast cancer susceptibility and aggressiveness. BMC Cancer. 2010;10:283
77. Ma K, Yang L, Shen R, Kong B, Chen W, Liang J, et al. Th17 cells regulate the production of CXCL1 in breast cancer. International Immunopharmacology. 2018;56:320-329
78. Divella R, Daniele A, Savino E, Palma F, Bellizzi A, Giotta F, et al. Circulating levels of transforming growth factor-βeta (TGF-β) and chemokine (C-X-C motif) ligand-1 (CXCL1) as predictors of distant seeding of circulating tumor cells in patients with metastatic breast cancer. Anticancer Research. 2013;33:1491-1497
79. Ciummo SL, D'Antonio L, Sorrentino C, Fieni C, Lanuti P, Stassi G, et al. The C-X-C motif chemokine ligand 1 sustains breast cancer stem cell self-renewal and promotes tumor progression and immune escape programs. Frontiers in Cell and Development Biology. 2021;9:689286
80. Wang F, Yuan C, Wu HZ, Liu B, Yang YF. Bioinformatics, molecular docking and experiments In vitro analyze the prognostic value of CXC chemokines in breast cancer. Frontiers in Oncology. 2021;11:665080
81. Zou A, Lambert D, Yeh H, Yasukawa K, Behbod F, Fan F, et al. Elevated CXCL1 expression in breast cancer stroma predicts poor prognosis and is inversely associated with expression of TGF-β signaling proteins. BMC Cancer. 2014;14:781
82. See AL, Chong PK, Lu SY, Lim YP. CXCL3 is a potential target for breast cancer metastasis. Current Cancer Drug Targets. 2014;14:294-309
83. Zhou J, Wu H, Su QX, Shi XK, Tang BW, Zhao CP, et al. Impacts of chemokine (C-X-C motif) receptor 2 C1208T polymorphism on cancer susceptibility. Journal of Immunology Research. 2021;2021:8727924
84. Boissière-Michot F, Jacot W, Massol O, Mollevi C, Lazennec G. CXCR2 levels correlate with immune infiltration and a better prognosis of triple-negative breast cancers. Cancers (Basel). 2021;13:2328
85. Boissière-Michot F, Jacot W, Fraisse J, Gourgou S, Timaxian C, Lazennec G. Prognostic value of CXCR2 in breast cancer. Cancers (Basel). 2020;12:2076
86. Xu H, Lin F, Wang Z, Yang L, Meng J, Ou Z, et al. CXCR2 promotes breast cancer metastasis and chemoresistance via suppression of AKT1 and activation of COX2. Cancer Letters. 2018;412:69-80
87. Razis E, Kalogeras KT, Kotsantis I, Koliou GA, Manousou K, Wirtz R, et al. The role of CXCL13 and CXCL9 in early breast cancer. Clinical Breast Cancer. 2020;20:e36-e53
88. Jafarzadeh A, Fooladseresht H, Nemati M, Assadollahi Z, Sheikhi A, Ghaderi A. Higher circulating levels of chemokine CXCL10 in patients with breast cancer: Evaluation of the influences of tumor stage and chemokine gene polymorphism. Cancer Biomarkers. 2016;16:545-554
89. Ejaeidi AA, Craft BS, Puneky LV, Lewis RE, Cruse JM. Hormone receptor-independent CXCL10 production is associated with the regulation of cellular factors linked to breast cancer progression and metastasis. Experimental and Molecular Pathology. 2015;99:163-172
90. Mulligan AM, Raitman I, Feeley L, Pinnaduwage D, Nguyen LT, O’Malley FP, et al. Tumoral lymphocytic infiltration and expression of the chemokine CXCL10 in breast cancers from the Ontario familial breast cancer registry. Clinical Cancer Research. 2013;19:336-346
91. Guo K, Feng G, Yan Q , Sun L, Zhang K, Shen F, et al. CXCR4 and CXCR3 are two distinct prognostic biomarkers in breast cancer: Database mining for CXCR family members. Molecular Medicine Reports. 2019;20:4791-4802
92. Saahene RO, Wang J, Wang ML, Agbo E, Song H. The role of CXC chemokine ligand 4/CXC chemokine receptor 3-B in breast cancer progression. Biotechnic & Histochemistry. 2019;94:53-59
93. Bronger H, Karge A, Dreyer T, Zech D, Kraeft S, Avril S, et al. Induction of cathepsin B by the CXCR3 chemokines CXCL9 and CXCL10 in human breast cancer cells. Oncology Letters. 2017;13:4224-4230
94. Zhu G, Yan HH, Pang Y, Jian J, Achyut BR, Liang X, et al. CXCR3 as a molecular target in breast cancer metastasis: Inhibition of tumor cell migration and promotion of host anti-tumor immunity. Oncotarget. 2015;6:43408-43419
95. Motyka J, Gacuta E, Kicman A, Kulesza M, Malinowski P, Ławicki S. CXCL12 and CXCR4 as potential early biomarkers for luminal A and luminal B subtypes of breast cancer. Cancer Management and Research. 2023;15:573-589
96. Yan M, Jene N, Byrne D, Millar EK, O'Toole SA, McNeil CM, et al. Recruitment of regulatory T cells is correlated with hypoxia-induced CXCR4 expression, and is associated with poor prognosis in basal-like breast cancers. Breast Cancer Research. 2011;13:R47
97. Hassan S, Ferrario C, Saragovi U, Quenneville L, Gaboury L, Baccarelli A, et al. The influence of tumor-host interactions in the stromal cell-derived factor-1/CXCR4 ligand/receptor axis in determining metastatic risk in breast cancer. The American Journal of Pathology. 2009;175:66-73
98. Mirisola V, Zuccarino A, Bachmeier BE, Sormani MP, Falter J, Nerlich A, et al. CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival. European Journal of Cancer. 2009;45:2579-2587
99. Zhao S, Chang SL, Linderman JJ, Feng FY, Luker GD. A comprehensive analysis of CXCL12 isoforms in breast cancer(1,2). Translational Oncology. 2014;7:429-438
100. Dayer R, Babashah S, Jamshidi S, Sadeghizadeh M. Upregulation of CXC chemokine receptor 4-CXC chemokine ligand 12 axis ininvasive breast carcinoma: A potent biomarker predicting lymph node metastasis. Journal of Cancer Research and Therapeutics. 2018;14:345-350
101. Potter SM, Dwyer RM, Curran CE, Hennessy E, Harrington KA, Griffin DG, et al. Systemic chemokine levels in breast cancer patients and their relationship with circulating menstrual hormones. Breast Cancer Research and Treatment. 2009;115:279-287
102. Kang H, Watkins G, Parr C, Douglas-Jones A, Mansel RE, Jiang WG. Stromal cell derived factor-1: Its influence on invasiveness and migration of breast cancer cells in vitro, and its association with prognosis and survival in human breast cancer. Breast Cancer Research. 2005;7:R402-R410
103. Zhang Z, Ni C, Chen W, Wu P, Wang Z, Yin J, et al. Expression of CXCR4 and breast cancer prognosis: A systematic review and meta-analysis. BMC Cancer. 2014;14:49
104. Zhang M, Liu HX, Teng XD, Wang HB, Cui J, Jia SS, et al. The differences in CXCR4 protein expression are significant for the five molecular subtypes of breast cancer. Ultrastructural Pathology. 2012;36:381-386
105. Hiller DJ, Meschonat C, Kim R, Li BD, Chu QD. Chemokine receptor CXCR4 level in primary tumors independently predicts outcome for patients with locally advanced breast cancer. Surgery. 2011;150:459-465
106. Mizell J, Smith M, Li BD, Ampil F, Chu QD. Overexpression of CXCR4 in primary tumor of patients with HER-2 negative breast cancer was predictive of a poor disease-free survival: A validation study. Annals of Surgical Oncology. 2009;16:2711-2716
107. Yasuoka H, Tsujimoto M, Yoshidome K, Nakahara M, Kodama R, Sanke T, et al. Cytoplasmic CXCR4 expression in breast cancer: Induction by nitric oxide and correlation with lymph node metastasis and poor prognosis. BMC Cancer. 2008;8:340
108. Woo SU, Bae JW, Kim CH, Lee JB, Koo BW. A significant correlation between nuclear CXCR4 expression and axillary lymph node metastasis in hormonal receptor negative breast cancer. Annals of Surgical Oncology. 2008;15:281-285
109. Holm NT, Byrnes K, Li BD, Turnage RH, Abreo F, Mathis JM, et al. Elevated levels of chemokine receptor CXCR4 in HER-2 negative breast cancer specimens predict recurrence. The Journal of Surgical Research. 2007;141:53-59
110. Su YC, Wu MT, Huang CJ, Hou MF, Yang SF, Chai CY. Expression of CXCR4 is associated with axillary lymph node status in patients with early breast cancer. Breast. 2006;15:533-539
111. Holm NT, Abreo F, Johnson LW, Li BD, Chu QD. Elevated chemokine receptor CXCR4 expression in primary tumors following neoadjuvant chemotherapy predicts poor outcomes for patients with locally advanced breast cancer (LABC). Breast Cancer Research and Treatment. 2009;113:293-299
112. Zhao H, Guo L, Zhao H, Zhao J, Weng H, Zhao B. CXCR4 over-expression and survival in cancer: A system review and meta-analysis. Oncotarget. 2015;6:5022-5040
113. Kang H, Watkins G, Douglas-Jones A, Mansel RE, Jiang WG. The elevated level of CXCR4 is correlated with nodal metastasis of human breast cancer. Breast. 2005;14:360-367
114. Kato M, Kitayama J, Kazama S, Nagawa H. Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma. Breast Cancer Research. 2003;5:R144-R150
115. Rhodes LV, Short SP, Neel NF, Salvo VA, Zhu Y, Elliott S, et al. Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer. Cancer Research. 2011;71:603-613
116. Chu QD, Panu L, Holm NT, Li BD, Johnson LW, Zhang S. High chemokine receptor CXCR4 level in triple negative breast cancer specimens predicts poor clinical outcome. The Journal of Surgical Research. 2010;159:689-695
117. Ramos EA, Grochoski M, Braun-Prado K, Seniski GG, Cavalli IJ, Ribeiro EM, et al. Epigenetic changes of CXCR4 and its ligand CXCL12 as prognostic factors for sporadic breast cancer. PLoS One. 2011;6:e29461
118. Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M, et al. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell. 2004;6:459-469
119. Andre F, Xia W, Conforti R, Wei Y, Boulet T, Tomasic G, et al. CXCR4 expression in early breast cancer and risk of distant recurrence. The Oncologist. 2009;14:1182-1188
120. Chen HW, Du CW, Wei XL, Khoo US, Zhang GJ. Cytoplasmic CXCR4 high-expression exhibits distinct poor clinicopathological characteristics and predicts poor prognosis in triple-negative breast cancer. Current Molecular Medicine. 2013;13:410-416
121. Sivrikoz ON, Doganay L, Sivrikoz UK, Karaarslan S, Sanal SM. Distribution of CXCR4 and γ-catenin expression pattern in breast cancer subtypes and their relationship to axillary nodal involvement. Polish Journal of Pathology. 2013;64:253-259
122. Papatheodorou H, Papanastasiou AD, Sirinian C, Scopa C, Kalofonos HP, Leotsinidis M, et al. Expression patterns of SDF1/CXCR4 in human invasive breast carcinoma and adjacent normal stroma: Correlation with tumor clinicopathological parameters and patient survival. Pathology, Research and Practice. 2014;210:662-667
123. Schmid BC, Rudas M, Rezniczek GA, Leodolter S, Zeillinger R. CXCR4 is expressed in ductal carcinoma in situ of the breast and in atypical ductal hyperplasia. Breast Cancer Research and Treatment. 2004;84:247-250
124. Aravindan BK, Prabhakar J, Somanathan T, Subhadra L. The role of chemokine receptor 4 and its ligand stromal cell derived factor 1 in breast cancer. Annals of Translational Medicine. 2015;3:23
125. Xu TP, Shen H, Liu LX, Shu YQ. The impact of chemokine receptor CXCR4 on breast cancer prognosis: A meta-analysis. Cancer Epidemiology. 2013;37:725-731
126. Biswas S, Sengupta S, Roy Chowdhury S, Jana S, Mandal G, Mandal PK, et al. CXCL13-CXCR5 co-expression regulates epithelial to mesenchymal transition of breast cancer cells during lymph node metastasis. Breast Cancer Research and Treatment. 2014;143:265-276
127. Tang Z, Yu M, Miller F, Berk RS, Tromp G, Kosir MA. Increased invasion through basement membrane by CXCL7-transfected breast cells. American Journal of Surgery. 2008;196:690-696
128. Gibbs C, So JY, Ahad A, Michalowski AM, Son DS, Li Y. CXCL14 attenuates triple-negative breast cancer progression by regulating immune profiles of the tumor microenvironment in a T cell-dependent manner. International Journal of Molecular Sciences. 2022;23:9314
129. Gu XL, Ou ZL, Lin FJ, Yang XL, Luo JM, Shen ZZ, et al. Expression of CXCL14 and its anticancer role in breast cancer. Breast Cancer Research and Treatment. 2012;135:725-735
130. Wani N, Nasser MW, Ahirwar DK, Zhao H, Miao Z, Shilo K, et al. C-X-C motif chemokine 12/C-X-C chemokine receptor type 7 signaling regulates breast cancer growth and metastasis by modulating the tumor microenvironment. Breast Cancer Research. 2014;16:R54
131. Shams R, Seifi-Alan M, Bandehpour M, Omrani MD, Ghafouri-Fard S. C-X-C chemokine receptor type 7 (CXCR-7) expression in invasive ductal carcinoma of breast in association with clinicopathological features. Pathology Oncology Research. 2020;26:1015-1020
132. Park MH, Lee JS, Yoon JH. High expression of CX3CL1 by tumor cells correlates with a good prognosis and increased tumor-infiltrating CD8+ T cells, natural killer cells, and dendritic cells in breast carcinoma. Journal of Surgical Oncology. 2012;106:386-392
133. Tsang JY, Ni YB, Chan SK, Shao MM, Kwok YK, Chan KW, et al. CX3CL1 expression is associated with poor outcome in breast cancer patients. Breast Cancer Research and Treatment. 2013;140:495-504

[1] 1. Masih M, Agarwal S, Kaur R, Gautam PK. Role of chemokines in breast cancer. Cytokine. 2022;155:155909

[2] 2. Jézéquel P, Gouraud W, Ben Azzouz F, Guérin-Charbonnel C, Juin PP, Lasla H, et al. Bc-GenExMiner 4.5: New mining module computes breast cancer differential gene expression analyses. Database: The Journal of Biological Databases and Curation. 2021;2021:baab007

[3] 3. Győrffy B. Survival analysis across the entire transcriptome identifies biomarkers with the highest prognostic power in breast cancer. Computational and Structural Biotechnology Journal. 2021;19:4101-4109

[4] 4. Bessaad M, Habel A, Hadj Ahmed M, Xu W, Stayoussef M, Bouaziz H, et al. Assessing serum cytokine profiles in inflammatory breast cancer patients using Luminex® technology. Cytokine. 2023;172:156409

[5] 5. Chavey C, Bibeau F, Gourgou-Bourgade S, Burlinchon S, Boissière F, Laune D, et al. Oestrogen receptor negative breast cancers exhibit high cytokine content. Breast Cancer Research. 2007;9:R15

[6] 6. Chen B, Zhang S, Li Q , Wu S, He H, Huang J. Bioinformatics identification of CCL8/21 as potential prognostic biomarkers in breast cancer microenvironment. Bioscience Reports. 2020;40:BSR20202042

[7] 7. Bièche I, Lerebours F, Tozlu S, Espie M, Marty M, Lidereau R. Molecular profiling of inflammatory breast cancer: Identification of a poor-prognosis gene expression signature. Clinical Cancer Research. 2004;10:6789-6795

[8] 8. Franzén B, Alexeyenko A, Kamali-Moghaddam M, Hatschek T, Kanter L, Ramqvist T, et al. Protein profiling of fine-needle aspirates reveals subtype-associated immune signatures and involvement of chemokines in breast cancer. Molecular Oncology. 2019;13:376-391

[9] 9. Farmaki E, Kaza V, Papavassiliou AG, Chatzistamou I, Kiaris H. Induction of the MCP chemokine cluster cascade in the periphery by cancer cell-derived Ccl3. Cancer Letters. 2017;389:49-58

[10] 10. Hozhabri H, Moghaddam MM, Moghaddam MM, Mohammadian A. A comprehensive bioinformatics analysis to identify potential prognostic biomarkers among CC and CXC chemokines in breast cancer. Scientific Reports. 2022;12:10374

[11] 11. Yu X, Zhang Y, Lin Y, Zou S, Zhu P, Song M, et al. The association between plasma chemokines and breast cancer risk and prognosis: A mendelian randomization study. Frontiers in Genetics. 2022;13:1004931

[12] 12. Thomas JK, Mir H, Kapur N, Bae S, Singh S. CC chemokines are differentially expressed in breast cancer and are associated with disparity in overall survival. Scientific Reports. 2019;9:4014

[13] 13. Yamaguchi M, Takagi K, Narita K, Miki Y, Onodera Y, Miyashita M, et al. Stromal CCL5 promotes breast cancer progression by interacting with CCR3 in tumor cells. International Journal of Molecular Sciences. 2021;22:1918

[14] 14. Zazo S, González-Alonso P, Martín-Aparicio E, Chamizo C, Luque M, Sanz-Álvarez M, et al. Autocrine CCL5 effect mediates trastuzumab resistance by ERK pathway activation in HER2-positive breast cancer. Molecular Cancer Therapeutics. 2020;19:1696-1707

[15] 15. Luboshits G, Shina S, Kaplan O, Engelberg S, Nass D, Lifshitz-Mercer B, et al. Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma. Cancer Research. 1999;59:4681-4687

[16] 16. Zhang Y, Yao F, Yao X, Yi C, Tan C, Wei L, et al. Role of CCL5 in invasion, proliferation and proportion of CD44+/CD24- phenotype of MCF-7 cells and correlation of CCL5 and CCR5 expression with breast cancer progression. Oncology Reports. 2009;21:1113-1121

[17] 17. Velasco-Velázquez M, Jiao X, De La Fuente M, Pestell TG, Ertel A, Lisanti MP, et al. CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Research. 2012;72:3839-3850

[18] 18. Zhang Q , Qin J, Zhong L, Gong L, Zhang B, Zhang Y, et al. CCL5-mediated Th2 immune polarization promotes metastasis in luminal breast cancer. Cancer Research. 2015;75:4312-4321

[19] 19. Derossi DR, Amarante MK, Guembarovski RL, de Oliveira CEC, Suzuki KM, Watanabe MAE, et al. CCL5 protein level: Influence on breast cancer staging and lymph nodes commitment. Molecular Biology Reports. 2019;46:6165-6170

[20] 20. Narita D, Seclaman E, Anghel A, Ilina R, Cireap N, Negru S, et al. Altered levels of plasma chemokines in breast cancer and their association with clinical and pathological characteristics. Neoplasma. 2016;63:141-149

[21] 21. Farmaki E, Chatzistamou I, Kaza V, Kiaris H. A CCL8 gradient drives breast cancer cell dissemination. Oncogene. 2016;35:6309-6318

[22] 22. Mehraj U, Alshehri B, Khan AA, Bhat AA, Bagga P, Wani NA, et al. Expression pattern and prognostic significance of chemokines in breast cancer: An integrated bioinformatics analysis. Clinical Breast Cancer. 2022;22:567-578

[23] 23. Li X, Wang M, Gong T, Lei X, Hu T, Tian M, et al. A S100A14-CCL2/CXCL5 signaling axis drives breast cancer metastasis. Theranostics. 2020;10:5687-5703

[24] 24. Valković T, Lucin K, Krstulja M, Dobi-Babić R, Jonjić N. Expression of monocyte chemotactic protein-1 in human invasive ductal breast cancer. Pathology, Research and Practice. 1998;194:335-340

[25] 25. Ueno T, Toi M, Saji H, Muta M, Bando H, Kuroi K, et al. Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clinical Cancer Research. 2000;6:3282-3289

[26] 26. Saji H, Koike M, Yamori T, Saji S, Seiki M, Matsushima K, et al. Significant correlation of monocyte chemoattractant protein-1 expression with neovascularization and progression of breast carcinoma. Cancer. 2001;92:1085-1091

[27] 27. Valković T, Fuckar D, Stifter S, Matusan K, Hasan M, Dobrila F, et al. Macrophage level is not affected by monocyte chemotactic protein-1 in invasive ductal breast carcinoma. Journal of Cancer Research and Clinical Oncology. 2005;131:453-458

[28] 28. Fujimoto H, Sangai T, Ishii G, Ikehara A, Nagashima T, Miyazaki M, et al. Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. International Journal of Cancer. 2009;125:1276-1284

[29] 29. Katanov C, Lerrer S, Liubomirski Y, Leider-Trejo L, Meshel T, Bar J, et al. Regulation of the inflammatory profile of stromal cells in human breast cancer: Prominent roles for TNF-α and the NF-κB pathway. Stem Cell Research & Therapy. 2015;6:87

[30] 30. Li D, Ji H, Niu X, Yin L, Wang Y, Gu Y, et al. Tumor-associated macrophages secrete CC-chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer. Cancer Science. 2020;111:47-58

[31] 31. Dwyer RM, Potter-Beirne SM, Harrington KA, Lowery AJ, Hennessy E, Murphy JM, et al. Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clinical Cancer Research. 2007;13:5020-5027

[32] 32. Dutta P, Sarkissyan M, Paico K, Wu Y, Vadgama JV. MCP-1 is overexpressed in triple-negative breast cancers and drives cancer invasiveness and metastasis. Breast Cancer Research and Treatment. 2018;170:477-486

[33] 33. Fang WB, Sofia Acevedo D, Smart C, Zinda B, Alissa N, Warren K, et al. Expression of CCL2/CCR2 signaling proteins in breast carcinoma cells is associated with invasive progression. Scientific Reports. 2021;11:8708

[34] 34. Fang WB, Yao M, Jokar I, Alhakamy N, Berkland C, Chen J, et al. The CCL2 chemokine is a negative regulator of autophagy and necrosis in luminal B breast cancer cells. Breast Cancer Research and Treatment. 2015;150:309-320

[35] 35. Cui K, Song N, Fan Y, Zeng L, Shi P, Wang Z, et al. A two-sample Mendelian randomization analysis: Causal association between chemokines and pan-carcinoma. Frontiers in Genetics. 2023;14:1285274

[36] 36. Lebrecht A, Grimm C, Lantzsch T, Ludwig E, Hefler L, Ulbrich E, et al. Monocyte chemoattractant protein-1 serum levels in patients with breast cancer. Tumour Biology. 2004;25:14-17

[37] 37. Wang J, Zhuang ZG, Xu SF, He Q , Shao YG, Ji M, et al. Expression of CCL2 is significantly different in five breast cancer genotypes and predicts patient outcome. International Journal of Clinical and Experimental Medicine. 2015;8:15684-15691

[38] 38. Heiskala M, Leidenius M, Joensuu K, Heikkilä P. High expression of CCL2 in tumor cells and abundant infiltration with CD14 positive macrophages predict early relapse in breast cancer. Virchows Archiv. 2019;474:3-12

[39] 39. Lubowicka E, Przylipiak A, Zajkowska M, Piskór BM, Malinowski P, Fiedorowicz W, et al. Plasma chemokine CCL2 and its receptor CCR2 concentrations as diagnostic biomarkers for breast cancer patients. BioMed Research International. 2018;2018:2124390

[40] 40. Xu M, Li Y, Li W, Zhao Q , Zhang Q , Le K, et al. Immune and stroma related genes in breast cancer: A comprehensive analysis of tumor microenvironment based on the cancer genome atlas (TCGA) database. Frontiers in Medicine (Lausanne). 2020;7:64

[41] 41. Seo EH, Namgung JH, Oh CS, Kim SH, Lee SH. Association of Chemokines and Chemokine Receptor Expression with Monocytic-myeloid-derived suppressor cells during tumor progression. Immune Network. 2018;18:e23

[42] 42. Kuehnemuth B, Piseddu I, Wiedemann GM, Lauseker M, Kuhn C, Hofmann S, et al. CCL1 is a major regulatory T cell attracting factor in human breast cancer. BMC Cancer. 2018;18:1278

[43] 43. Li JY, Ou ZL, Yu SJ, Gu XL, Yang C, Chen AX, et al. The chemokine receptor CCR4 promotes tumor growth and lung metastasis in breast cancer. Breast Cancer Research and Treatment. 2012;131:837-848

[44] 44. de Araújo RA, da Luz FAC, da Costa ME, Nascimento CP, Mendes TR, Mosca ERT, et al. The elusive luminal B breast cancer and the mysterious chemokines. Journal of Cancer Research and Clinical Oncology. 2023;149:12807-12819

[45] 45. Chen J, Yao Y, Gong C, Yu F, Su S, Chen J, et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. 2011;19:541-555

[46] 46. Lee SK, Park KK, Kim HJ, Park J, Son SH, Kim KR, et al. Human antigen R-regulated CCL20 contributes to osteolytic breast cancer bone metastasis. Scientific Reports. 2017;7:9610

[47] 47. Chen W, Qin Y, Wang D, Zhou L, Liu Y, Chen S, et al. CCL20 triggered by chemotherapy hinders the therapeutic efficacy of breast cancer. PLoS Biology. 2018;16:e2005869

[48] 48. Andre F, Cabioglu N, Assi H, Sabourin JC, Delaloge S, Sahin A, et al. Expression of chemokine receptors predicts the site of metastatic relapse in patients with axillary node positive primary breast cancer. Annals of Oncology. 2006;17:945-951

[49] 49. Cassier PA, Treilleux I, Bachelot T, Ray-Coquard I, Bendriss-Vermare N, Ménétrier-Caux C, et al. Prognostic value of the expression of C-chemokine receptor 6 and 7 and their ligands in non-metastatic breast cancer. BMC Cancer. 2011;11:213

[50] 50. Mohammed MM, Shaker O, Ramzy MM, Gaber SS, Kamel HS, Abed El Baky MF. The relation between ACKR4 and CCR7 genes expression and breast cancer metastasis. Life Sciences. 2021;279:119691

[51] 51. Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50-56

[52] 52. Li F, Zou Z, Suo N, Zhang Z, Wan F, Zhong G, et al. CCL21/CCR7 axis activating chemotaxis accompanied with epithelial-mesenchymal transition in human breast carcinoma. Medical Oncology. 2014;31:180

[53] 53. Gurgel DC, Wong DVT, Bandeira AM, Pereira JFB, Gomes-Filho JV, Pereira AC, et al. Cytoplasmic CCR7 (CCR7c) immunoexpression is associated with local tumor recurrence in triple-negative breast cancer. Pathology, Research and Practice. 2020;216:153265

[54] 54. Liu Y, Ji R, Li J, Gu Q , Zhao X, Sun T, et al. Correlation effect of EGFR and CXCR4 and CCR7 chemokine receptors in predicting breast cancer metastasis and prognosis. Journal of Experimental & Clinical Cancer Research. 2010;29:16

[55] 55. Cabioglu N, Yazici MS, Arun B, Broglio KR, Hortobagyi GN, Price JE, et al. CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer. Clinical Cancer Research. 2005;11:5686-5693

[56] 56. Sonbul SN, Gorringe KL, Aleskandarany MA, Mukherjee A, Green AR, Ellis IO, et al. Chemokine (C-C motif) receptor 7 (CCR7) associates with the tumour immune microenvironment but not progression in invasive breast carcinoma. The Journal of Pathology. Clinical Research. 2017;3:105-114

[57] 57. Wu J, Li L, Liu J, Wang Y, Wang Z, Wang Y, et al. CC chemokine receptor 7 promotes triple-negative breast cancer growth and metastasis. Acta Biochimica et Biophysica Sinica (Shanghai). 2018;50:835-842

[58] 58. Li X, Sun S, Li N, Gao J, Yu J, Zhao J, et al. High expression of CCR7 predicts lymph node metastasis and good prognosis in triple negative breast cancer. Cellular Physiology and Biochemistry. 2017;43:531-539

[59] 59. Strien L, Joensuu K, Heikkilä P, Leidenius MH. Different expression patterns of CXCR4, CCR7, Maspin and FOXP3 in luminal breast cancers and their sentinel node metastases. Anticancer Research. 2017;37:175-182

[60] 60. Vahedi L, Ghasemi M, Yazdani J, Ranjbar S, Nouri B, Alizadeh A, et al. Investigation of CCR7 marker expression using immunohistochemical method and its association with clinicopathologic properties in patients with breast cancer. International Journal of Hematology-Oncology and Stem Cell Research. 2018;12:103-110

[61] 61. Johnson-Holiday C, Singh R, Johnson E, Singh S, Stockard CR, Grizzle WE, et al. CCL25 mediates migration, invasion and matrix metalloproteinase expression by breast cancer cells in a CCR9-dependent fashion. International Journal of Oncology. 2011;38:1279-1285

[62] 62. Li L, Yao W, Yan S, Dong X, Lv Z, Jing Q , et al. Pan-cancer analysis of prognostic and immune infiltrates for CXCs. Cancers (Basel). 2021;13:4153

[63] 63. Bièche I, Chavey C, Andrieu C, Busson M, Vacher S, Le Corre L, et al. CXC chemokines located in the 4q21 region are up-regulated in breast cancer. Endocrine-Related Cancer. 2007;14:1039-1052

[64] 64. Chen E, Qin X, Peng K, Xu X, Li W, Cheng X, et al. Identification of potential therapeutic targets among CXC chemokines in breast tumor microenvironment using integrative bioinformatics analysis. Cellular Physiology and Biochemistry. 2018;45:1731-1746

[65] 65. Li Y, Liang M, Lin Y, Lv J, Chen M, Zhou P, et al. Transcriptional expressions of CXCL9/10/12/13 as prognosis factors in breast cancer. Journal of Oncology. 2020;2020:4270957

[66] 66. Wang YH, Shen CY, Lin SC, Kuo WH, Kuo YT, Hsu YL, et al. Monocytes secrete CXCL7 to promote breast cancer progression. Cell Death & Disease. 2021;12:1090

[67] 67. Motyka J, Gacuta E, Kicman A, Kulesza M, Ławicki P, Ławicki S. Plasma levels of CXC motif chemokine 1 (CXCL1) and chemokine 8 (CXCL8) as diagnostic biomarkers in luminal A and B breast cancer. Journal of Clinical Medicine. 2022;11:6694

[68] 68. Fang QI, Wang X, Luo G, Yu M, Zhang X, Xu N. Increased CXCL8 expression is negatively correlated with the overall survival of patients with ER-negative breast cancer. Anticancer Research. 2017;37:4845-4852

[69] 69. Milovanovic J, Todorovic-Rakovic N, Abu RZ. The prognostic role of interleukin-8 (IL-8) and matrix metalloproteinases −2 and −9 in lymph node-negative untreated breast cancer patients. JBUON. 2013;18:866-873

[70] 70. Benoy IH, Salgado R, Van Dam P, Geboers K, Van Marck E, Scharpé S, et al. Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival. Clinical Cancer Research. 2004;10:7157-7162

[71] 71. Ma Y, Ren Y, Dai ZJ, Wu CJ, Ji YH, Xu J. IL-6, IL-8 and TNF-α levels correlate with disease stage in breast cancer patients. Advances in Clinical and Experimental Medicine. 2017;26:421-426

[72] 72. Celik B, Yalcin AD, Genc GE, Bulut T, Kuloglu Genc S, Gumuslu S. CXCL8, IL-1β and sCD200 are pro-inflammatory cytokines and their levels increase in the circulation of breast carcinoma patients. Biomedical Report. 2016;5:259-263

[73] 73. Tiainen L, Hämäläinen M, Luukkaala T, Tanner M, Lahdenperä O, Vihinen P, et al. Low plasma IL-8 levels during chemotherapy are predictive of excellent long-term survival in metastatic breast cancer. Clinical Breast Cancer. 2019;19:e522-e533

[74] 74. König A, Vilsmaier T, Rack B, Friese K, Janni W, Jeschke U, et al. Determination of Interleukin-4, −5, −6, −8 and −13 in serum of patients with breast cancer before treatment and its correlation to circulating tumor cells. Anticancer Research. 2016;36:3123-3130

[75] 75. Razmkhah M, Jaberipour M, Safaei A, Talei AR, Erfani N, Ghaderi A. Chemokine and chemokine receptors: A comparative study between metastatic and nonmetastatic lymph nodes in breast cancer patients. European Cytokine Network. 2012;23:72-77

[76] 76. Snoussi K, Mahfoudh W, Bouaouina N, Fekih M, Khairi H, Helal AN, et al. Combined effects of IL-8 and CXCR2 gene polymorphisms on breast cancer susceptibility and aggressiveness. BMC Cancer. 2010;10:283

[77] 77. Ma K, Yang L, Shen R, Kong B, Chen W, Liang J, et al. Th17 cells regulate the production of CXCL1 in breast cancer. International Immunopharmacology. 2018;56:320-329

[78] 78. Divella R, Daniele A, Savino E, Palma F, Bellizzi A, Giotta F, et al. Circulating levels of transforming growth factor-βeta (TGF-β) and chemokine (C-X-C motif) ligand-1 (CXCL1) as predictors of distant seeding of circulating tumor cells in patients with metastatic breast cancer. Anticancer Research. 2013;33:1491-1497

[79] 79. Ciummo SL, D'Antonio L, Sorrentino C, Fieni C, Lanuti P, Stassi G, et al. The C-X-C motif chemokine ligand 1 sustains breast cancer stem cell self-renewal and promotes tumor progression and immune escape programs. Frontiers in Cell and Development Biology. 2021;9:689286

[80] 80. Wang F, Yuan C, Wu HZ, Liu B, Yang YF. Bioinformatics, molecular docking and experiments In vitro analyze the prognostic value of CXC chemokines in breast cancer. Frontiers in Oncology. 2021;11:665080

[81] 81. Zou A, Lambert D, Yeh H, Yasukawa K, Behbod F, Fan F, et al. Elevated CXCL1 expression in breast cancer stroma predicts poor prognosis and is inversely associated with expression of TGF-β signaling proteins. BMC Cancer. 2014;14:781

[82] 82. See AL, Chong PK, Lu SY, Lim YP. CXCL3 is a potential target for breast cancer metastasis. Current Cancer Drug Targets. 2014;14:294-309

[83] 83. Zhou J, Wu H, Su QX, Shi XK, Tang BW, Zhao CP, et al. Impacts of chemokine (C-X-C motif) receptor 2 C1208T polymorphism on cancer susceptibility. Journal of Immunology Research. 2021;2021:8727924

[84] 84. Boissière-Michot F, Jacot W, Massol O, Mollevi C, Lazennec G. CXCR2 levels correlate with immune infiltration and a better prognosis of triple-negative breast cancers. Cancers (Basel). 2021;13:2328

[85] 85. Boissière-Michot F, Jacot W, Fraisse J, Gourgou S, Timaxian C, Lazennec G. Prognostic value of CXCR2 in breast cancer. Cancers (Basel). 2020;12:2076

[86] 86. Xu H, Lin F, Wang Z, Yang L, Meng J, Ou Z, et al. CXCR2 promotes breast cancer metastasis and chemoresistance via suppression of AKT1 and activation of COX2. Cancer Letters. 2018;412:69-80

[87] 87. Razis E, Kalogeras KT, Kotsantis I, Koliou GA, Manousou K, Wirtz R, et al. The role of CXCL13 and CXCL9 in early breast cancer. Clinical Breast Cancer. 2020;20:e36-e53

[88] 88. Jafarzadeh A, Fooladseresht H, Nemati M, Assadollahi Z, Sheikhi A, Ghaderi A. Higher circulating levels of chemokine CXCL10 in patients with breast cancer: Evaluation of the influences of tumor stage and chemokine gene polymorphism. Cancer Biomarkers. 2016;16:545-554

[89] 89. Ejaeidi AA, Craft BS, Puneky LV, Lewis RE, Cruse JM. Hormone receptor-independent CXCL10 production is associated with the regulation of cellular factors linked to breast cancer progression and metastasis. Experimental and Molecular Pathology. 2015;99:163-172

[90] 90. Mulligan AM, Raitman I, Feeley L, Pinnaduwage D, Nguyen LT, O’Malley FP, et al. Tumoral lymphocytic infiltration and expression of the chemokine CXCL10 in breast cancers from the Ontario familial breast cancer registry. Clinical Cancer Research. 2013;19:336-346

[91] 91. Guo K, Feng G, Yan Q , Sun L, Zhang K, Shen F, et al. CXCR4 and CXCR3 are two distinct prognostic biomarkers in breast cancer: Database mining for CXCR family members. Molecular Medicine Reports. 2019;20:4791-4802

[92] 92. Saahene RO, Wang J, Wang ML, Agbo E, Song H. The role of CXC chemokine ligand 4/CXC chemokine receptor 3-B in breast cancer progression. Biotechnic & Histochemistry. 2019;94:53-59

[93] 93. Bronger H, Karge A, Dreyer T, Zech D, Kraeft S, Avril S, et al. Induction of cathepsin B by the CXCR3 chemokines CXCL9 and CXCL10 in human breast cancer cells. Oncology Letters. 2017;13:4224-4230

[94] 94. Zhu G, Yan HH, Pang Y, Jian J, Achyut BR, Liang X, et al. CXCR3 as a molecular target in breast cancer metastasis: Inhibition of tumor cell migration and promotion of host anti-tumor immunity. Oncotarget. 2015;6:43408-43419

[95] 95. Motyka J, Gacuta E, Kicman A, Kulesza M, Malinowski P, Ławicki S. CXCL12 and CXCR4 as potential early biomarkers for luminal A and luminal B subtypes of breast cancer. Cancer Management and Research. 2023;15:573-589

[96] 96. Yan M, Jene N, Byrne D, Millar EK, O'Toole SA, McNeil CM, et al. Recruitment of regulatory T cells is correlated with hypoxia-induced CXCR4 expression, and is associated with poor prognosis in basal-like breast cancers. Breast Cancer Research. 2011;13:R47

[97] 97. Hassan S, Ferrario C, Saragovi U, Quenneville L, Gaboury L, Baccarelli A, et al. The influence of tumor-host interactions in the stromal cell-derived factor-1/CXCR4 ligand/receptor axis in determining metastatic risk in breast cancer. The American Journal of Pathology. 2009;175:66-73

[98] 98. Mirisola V, Zuccarino A, Bachmeier BE, Sormani MP, Falter J, Nerlich A, et al. CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival. European Journal of Cancer. 2009;45:2579-2587

[99] 99. Zhao S, Chang SL, Linderman JJ, Feng FY, Luker GD. A comprehensive analysis of CXCL12 isoforms in breast cancer(1,2). Translational Oncology. 2014;7:429-438

[100] 100. Dayer R, Babashah S, Jamshidi S, Sadeghizadeh M. Upregulation of CXC chemokine receptor 4-CXC chemokine ligand 12 axis ininvasive breast carcinoma: A potent biomarker predicting lymph node metastasis. Journal of Cancer Research and Therapeutics. 2018;14:345-350

[101] 101. Potter SM, Dwyer RM, Curran CE, Hennessy E, Harrington KA, Griffin DG, et al. Systemic chemokine levels in breast cancer patients and their relationship with circulating menstrual hormones. Breast Cancer Research and Treatment. 2009;115:279-287

[102] 102. Kang H, Watkins G, Parr C, Douglas-Jones A, Mansel RE, Jiang WG. Stromal cell derived factor-1: Its influence on invasiveness and migration of breast cancer cells in vitro, and its association with prognosis and survival in human breast cancer. Breast Cancer Research. 2005;7:R402-R410

[103] 103. Zhang Z, Ni C, Chen W, Wu P, Wang Z, Yin J, et al. Expression of CXCR4 and breast cancer prognosis: A systematic review and meta-analysis. BMC Cancer. 2014;14:49

[104] 104. Zhang M, Liu HX, Teng XD, Wang HB, Cui J, Jia SS, et al. The differences in CXCR4 protein expression are significant for the five molecular subtypes of breast cancer. Ultrastructural Pathology. 2012;36:381-386

[105] 105. Hiller DJ, Meschonat C, Kim R, Li BD, Chu QD. Chemokine receptor CXCR4 level in primary tumors independently predicts outcome for patients with locally advanced breast cancer. Surgery. 2011;150:459-465

[106] 106. Mizell J, Smith M, Li BD, Ampil F, Chu QD. Overexpression of CXCR4 in primary tumor of patients with HER-2 negative breast cancer was predictive of a poor disease-free survival: A validation study. Annals of Surgical Oncology. 2009;16:2711-2716

[107] 107. Yasuoka H, Tsujimoto M, Yoshidome K, Nakahara M, Kodama R, Sanke T, et al. Cytoplasmic CXCR4 expression in breast cancer: Induction by nitric oxide and correlation with lymph node metastasis and poor prognosis. BMC Cancer. 2008;8:340

[108] 108. Woo SU, Bae JW, Kim CH, Lee JB, Koo BW. A significant correlation between nuclear CXCR4 expression and axillary lymph node metastasis in hormonal receptor negative breast cancer. Annals of Surgical Oncology. 2008;15:281-285

[109] 109. Holm NT, Byrnes K, Li BD, Turnage RH, Abreo F, Mathis JM, et al. Elevated levels of chemokine receptor CXCR4 in HER-2 negative breast cancer specimens predict recurrence. The Journal of Surgical Research. 2007;141:53-59

[110] 110. Su YC, Wu MT, Huang CJ, Hou MF, Yang SF, Chai CY. Expression of CXCR4 is associated with axillary lymph node status in patients with early breast cancer. Breast. 2006;15:533-539

[111] 111. Holm NT, Abreo F, Johnson LW, Li BD, Chu QD. Elevated chemokine receptor CXCR4 expression in primary tumors following neoadjuvant chemotherapy predicts poor outcomes for patients with locally advanced breast cancer (LABC). Breast Cancer Research and Treatment. 2009;113:293-299

[112] 112. Zhao H, Guo L, Zhao H, Zhao J, Weng H, Zhao B. CXCR4 over-expression and survival in cancer: A system review and meta-analysis. Oncotarget. 2015;6:5022-5040

[113] 113. Kang H, Watkins G, Douglas-Jones A, Mansel RE, Jiang WG. The elevated level of CXCR4 is correlated with nodal metastasis of human breast cancer. Breast. 2005;14:360-367

[114] 114. Kato M, Kitayama J, Kazama S, Nagawa H. Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma. Breast Cancer Research. 2003;5:R144-R150

[115] 115. Rhodes LV, Short SP, Neel NF, Salvo VA, Zhu Y, Elliott S, et al. Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer. Cancer Research. 2011;71:603-613

[116] 116. Chu QD, Panu L, Holm NT, Li BD, Johnson LW, Zhang S. High chemokine receptor CXCR4 level in triple negative breast cancer specimens predicts poor clinical outcome. The Journal of Surgical Research. 2010;159:689-695

[117] 117. Ramos EA, Grochoski M, Braun-Prado K, Seniski GG, Cavalli IJ, Ribeiro EM, et al. Epigenetic changes of CXCR4 and its ligand CXCL12 as prognostic factors for sporadic breast cancer. PLoS One. 2011;6:e29461

[118] 118. Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M, et al. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell. 2004;6:459-469

[119] 119. Andre F, Xia W, Conforti R, Wei Y, Boulet T, Tomasic G, et al. CXCR4 expression in early breast cancer and risk of distant recurrence. The Oncologist. 2009;14:1182-1188

[120] 120. Chen HW, Du CW, Wei XL, Khoo US, Zhang GJ. Cytoplasmic CXCR4 high-expression exhibits distinct poor clinicopathological characteristics and predicts poor prognosis in triple-negative breast cancer. Current Molecular Medicine. 2013;13:410-416

[121] 121. Sivrikoz ON, Doganay L, Sivrikoz UK, Karaarslan S, Sanal SM. Distribution of CXCR4 and γ-catenin expression pattern in breast cancer subtypes and their relationship to axillary nodal involvement. Polish Journal of Pathology. 2013;64:253-259

[122] 122. Papatheodorou H, Papanastasiou AD, Sirinian C, Scopa C, Kalofonos HP, Leotsinidis M, et al. Expression patterns of SDF1/CXCR4 in human invasive breast carcinoma and adjacent normal stroma: Correlation with tumor clinicopathological parameters and patient survival. Pathology, Research and Practice. 2014;210:662-667

[123] 123. Schmid BC, Rudas M, Rezniczek GA, Leodolter S, Zeillinger R. CXCR4 is expressed in ductal carcinoma in situ of the breast and in atypical ductal hyperplasia. Breast Cancer Research and Treatment. 2004;84:247-250

[124] 124. Aravindan BK, Prabhakar J, Somanathan T, Subhadra L. The role of chemokine receptor 4 and its ligand stromal cell derived factor 1 in breast cancer. Annals of Translational Medicine. 2015;3:23

[125] 125. Xu TP, Shen H, Liu LX, Shu YQ. The impact of chemokine receptor CXCR4 on breast cancer prognosis: A meta-analysis. Cancer Epidemiology. 2013;37:725-731

[126] 126. Biswas S, Sengupta S, Roy Chowdhury S, Jana S, Mandal G, Mandal PK, et al. CXCL13-CXCR5 co-expression regulates epithelial to mesenchymal transition of breast cancer cells during lymph node metastasis. Breast Cancer Research and Treatment. 2014;143:265-276

[127] 127. Tang Z, Yu M, Miller F, Berk RS, Tromp G, Kosir MA. Increased invasion through basement membrane by CXCL7-transfected breast cells. American Journal of Surgery. 2008;196:690-696

[128] 128. Gibbs C, So JY, Ahad A, Michalowski AM, Son DS, Li Y. CXCL14 attenuates triple-negative breast cancer progression by regulating immune profiles of the tumor microenvironment in a T cell-dependent manner. International Journal of Molecular Sciences. 2022;23:9314

[129] 129. Gu XL, Ou ZL, Lin FJ, Yang XL, Luo JM, Shen ZZ, et al. Expression of CXCL14 and its anticancer role in breast cancer. Breast Cancer Research and Treatment. 2012;135:725-735

[130] 130. Wani N, Nasser MW, Ahirwar DK, Zhao H, Miao Z, Shilo K, et al. C-X-C motif chemokine 12/C-X-C chemokine receptor type 7 signaling regulates breast cancer growth and metastasis by modulating the tumor microenvironment. Breast Cancer Research. 2014;16:R54

[131] 131. Shams R, Seifi-Alan M, Bandehpour M, Omrani MD, Ghafouri-Fard S. C-X-C chemokine receptor type 7 (CXCR-7) expression in invasive ductal carcinoma of breast in association with clinicopathological features. Pathology Oncology Research. 2020;26:1015-1020

[132] 132. Park MH, Lee JS, Yoon JH. High expression of CX3CL1 by tumor cells correlates with a good prognosis and increased tumor-infiltrating CD8+ T cells, natural killer cells, and dendritic cells in breast carcinoma. Journal of Surgical Oncology. 2012;106:386-392

[133] 133. Tsang JY, Ni YB, Chan SK, Shao MM, Kwok YK, Chan KW, et al. CX3CL1 expression is associated with poor outcome in breast cancer patients. Breast Cancer Research and Treatment. 2013;140:495-504