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Open Access 18 Oct 2024Review
Roles of Chemokine Axes in Breast Cancer
Deok-Soo Son 1,*, Samuel E. Adunyah 1
Affiliation
Article Info

1 Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA

*Correspondence: dson@mmc.edu (Deok-Soo Son)

Abstract

Chemokines bind to specific chemokine receptors, known as cell surface G protein-coupled receptors, constructing chemokine axes which lead to cell migration and invasion in developmental stage, pathophysiological process, and immune reactions. The chemokine axes in the tumor microenvironment are involved in tumor growth, angiogenesis, cancer stem-like cell properties, metastasis, and chemoresistance, modifying tumor immune contexture and cancer progression. Clinical features, including tumor state, grade, lymph node metastasis, and cancer subtypes, are related to the specific chemokine axes, which play a significant role in immune contexture and cell to cell interaction in the tumor microenvironment, followed by altered cancer prognosis and overall survival. The present review summarizes the role of chemokine axes in breast cancer, based on data obtained from cell line and animal models and human tumor samples. This review provides information that understand the important roles of each chemokine axis in breast cancer, probably offering a clue of adjuvant therapeutic options to improve the quality of life and survival for patients with breast cancer.

Keywords

  • chemokines
  • breast
  • cancer
1. Introduction

The family of chemokines called chemotactic cytokines are small and secreted proteins that exert cellular signal pathways through cell surface G protein-coupled chemokine receptors [1]. Chemokines consist of 4 subfamilies according to the number of amino acids inserted between the first cysteine (C) motifs as follows: C (XCL1-2), CC (CCL1-28), CXC (CXCL1-17) and CX3C (CX3CL1). Except for orphan chemokines CCL18 and CXCL14, each chemokine recognizes its specific chemokine receptor (XCR1, CCR1-10, CXCR1-8, and CX3CR1) to create the unique chemokine axis as shown in Table 1, which controls angiogenesis, regulates immune network, and modulates cellular functions. In breast cancer, chemokines recruit immune cells into the tumor microenvironment through the chemokine axis between tumor and immune cells [2], developing immune contexture which changes cancer progression and prognosis.

Table 1. Human chemokine axes.
Chemokine axis family Chemokine axis subfamily
The XCL-XCR axis The XCL1/2-XCR1 axis
The CCL-CCR axes The CCL3/5/7/8/14/15/16/23-CCR1 axis
The CCL2/7/8/13/16-CCR2 axis
The CCL5/7/11/13/14/15/24/26/28-CCR3 axis
The CCL17/22-CCR4 axis
The CCL3/4/5/8/11/14/16-CCR5 axis
The CCL20-CCR6 axis
The CCL19/21-CCR7 axis
The CCL1/16-CCR8 axis
The CCL25-CCR9 axis
The CCL27/28-CCR10 axis
The CXCL-CXCR axes The CXCL6/7/8-CXCR1 axis
The CXCL1/2/3/5/6/7/8-CXCR2 axis
The CXCL4/9/10/11-CXCR3 axis
The CXCL12-CXCR4 axis
The CXCL13-CXCR5 axis
The CXCL16-CXCR6 axis
The CXCL11/12-CXCR7 axis
The CXCL17-CXCR8 axis
The CX3CL-CX3CR axis The CX3CL1-CX3CR1 axis

Orphan chemokines: CCL18, CXCL14. XCL-XCR, Lymphotactin-X-C motif chemokine receptor; CCL-CCR, Chemokine (C-C motif) ligand-Chemokine (C-C motif) receptor; CXCL-CXCR, Chemokine (C-X-C motif) ligand-Chemokine (C-X-C motif) receptor.

This review has described functional roles of chemokine axes in breast cancer based on literature data about effects of chemokines and chemokine receptors in cell lines, tumor-bearing animal models, and patients with breast cancer. Molecular subtypes of breast cancer are defined in large part by expression levels of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), as follows: luminal A (ER+/PR+/HER2-), luminal B (ER+/PR+/HER2+), HER2-enriched (ER-/PR-/HER2+), and basal-like (triple-negative, ER-/PR-/HER2-). Breast cancer cell models present in vitro results of each chemokine and chemokine receptor in breast cancer cell lines, which contain breast subtype cell lines, treatments including antibody (Ab), knockdown (KD), antagonists, overexpression, and inhibitors, cellular functions, and signaling (Table 2, Ref. [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104]). Breast cancer animal models show in vivo results of each chemokine and chemokine receptor in tumor-bearing animals, which contain breast subtype cell lines, animal models, treatments including Ab, KD, knockout (KO), antagonists, overexpression, and inhibitors, functional parameters, signaling, and immune contexture (Table 3, Ref. [3, 5, 12, 13, 16, 19, 20, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 36, 39, 41, 42, 43, 47, 53, 54, 59, 60, 64, 65, 66, 68, 69, 71, 74, 77, 78, 81, 83, 85, 87, 88, 89, 90, 91, 93, 96, 97, 100, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148]). Finally, human breast cancer samples show clinical results of each chemokine and chemokine receptor in patients with breast cancer, which contain biomarker, clinical correlation, immune contexture, prognosis, and overall survival (Table 4, Ref. [5, 8, 9, 13, 14, 17, 23, 32, 34, 35, 36, 43, 44, 47, 49, 50, 52, 53, 62, 64, 74, 82, 88, 94, 98, 100, 101, 102, 107, 111, 117, 131, 140, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248]). These results obtained from cell lines, animal models, and human tumor samples contribute to a clear understanding on the critical roles of each chemokine axis in breast cancer progression, probably offering a clue of adjuvant therapeutic options to target the specific chemokine axis using either agonists or antagonists as well as antibodies for patients with breast cancer.

Table 2. Roles of chemokines and chemokine receptors in cell line models.
Chemokines Cell lines Treatment Function Signaling References
CCL2 BT549 KD Invasion↓ MMP9↓; Vimentin↓; N-cadherin↓ [14, 15]
β-catenin↑
MDA-MB-231 Ab; KD Proliferation→; Invasion↓; Apoptosis↓; Migration↓↑; MSC-induced migration↓; Mammosphere↓ NOTCH↑; Caspase-3↓ [16, 18, 24, 26, 27, 28, 29]
MDA-MB-468 Ab Invasion↓
MDA-MB-361 Mammosphere↑ NOTCH↑ [16]
BT474 Ab; KD Viability↓; Necrosis↑; Autophagy↑; MSC-induced migration↓ Ki67↓; HMGB1↓; LC3B↑ [23, 24]
MCF10CA1d Growth↑; Apoptosis↓; G2/M phase↑ PCNA↑; p27KIP1↓ [15, 20]
BT-20
HCC1937 PCNA↑; p27KIP1↓; β-catenin↑
MCF10A Invasion↑ Vimentin↑; MMP9↑; ERO1-α↑ [21]
DCIS.com Growth↑; Invasion↑ E-cadherin↓; Twist1↑ [22]
SUM225 Growth→; Invasion→
MCF-7 Viability↑; Apoptosis↓; Invasion↑; Migration↑ pAkt↑; pmTOR↑; pErk↑; E-cadherin↓; β-catenin↑; NOTCH↑; pSmad3↑; MMP9↑; VEGF↑; Twist↑ [4, 14, 16, 17, 18, 19]
T47D Viability↑; Apoptosis↓; Migration→
ZR-75-1 Migration↑ [4]
A3250 KD Proliferation→; Colony formation→ [30]
4T1 (m) Apoptosis↓; Migration↑ Caspase-3↓; pSmad3↑; pErk↑; RhoA↑ [18]
PyVmT carcinoma cells KD Viability↓; Necrosis↑; Autophagy↑; Migration↓; Angiogenesis↓; Mφ recruitment↓ Caspase-3↓; Ki67↓ [23, 31]
Met-1 (m) Monocytes ± Ab Migration↑; Migration↓ with Ab [25]
CCL3 MCF-7 Migration↑ [4]
T47D Migration→
ZR-75-1 Migration↑
CCL4 MCF-7 Migration↑ [4]
T47D Migration→
ZR-75-1 Migration↑
CCL5 MDA-MB-231 Proliferation↑; Calcium flux↑; Migration↑; Invasion↑; Glucose uptake↑; Glycolysis↑; Intracellular ATP/pyruvate/G6P↑ pAkt↑; pmTOR↑; pGSK-3β↑; GLUT-1↑ [5, 6, 7]
Trastuzumab-resistant BT-474 KD Chemoresistance↓ [8]
MCF-7 Proliferation↑; Migration↑; Glycolysis↑; Intracellular ATP/pyruvate↑ GLUT-1↑; Mdm2↑; p21↑; pp38↑ [4, 6, 9, 10, 11]
T47D Migration→; Tamoxifen-induced cell death↓
ZR-75-1 Migration→
Tamoxifen-resistant MCF-7 KD Chemoresistance↓ pSTAT3↓; BCL-2↓; BCL-xL↓; PARP↑; Caspase-9↑
4T1 (m) KD Proliferation→ [12]
CCL8 MDA-MB-231 Migration↑ [13]
MDA-MB-468
E0771
CCL18 MDA-MB-231 Migration↑ [34]
CCL19 MDA-MB-231 Proliferation↑; Migration↑; Invasion↑ E‐cadherin↓; N-cadherin↑; Vimentin↑; pAkt↑; MMP2/9↑ [38]
MCF-7
PyVmT-CCR7 Proliferation→; Migration↑ [39]
CCL20 MDA-MB-231 Ab; KD Viability↓; Migration↓; Invasion↓; Colony↓; Chemoresistance↓ ALDH↓ [34, 35, 36, 37]
EV Viability↑→; Migration↑→; Invasion↑; Colony↑; Chemoresistance↑; Stemness↑; Tumorsphere↑ uPA activity↑; MMP1↑; MMP2↑; MMP9↑; RANKL↑; OPG↓; ALDH↑; NANOG↑; OCT4↑; SOX2↑; pPKCζ↑; pP38↑; pp65↑; ABCB1↑
BT549 Invasion↑ MMP2↑; MMP9↑
HCC38
SUM159 Chemoresistance↑; ↓ in Ab/ND pPKCζ↑; pP38↑; pp65↑; ABCB1↑
CCL21 MDA-MB-231 Migration↑; Invasion↑→; Apoptosis↓; Colony↑ TAP-1↑; TGF-β↓; FasL↓; E-cadherin↓; Slug↑; Vimentin↑; N-cadherin↑; pAkt↑; pErk↑; BclX↑; Bmf↓ [39, 40, 41, 42, 43, 44, 45, 46]
SKBR-3 HLA-1→; TAP-1→
HCC1428 Migration↑; Invasion↑ E-cadherin↓; Slug↑; Vimentin↑; N-cadherin↑
MCF7 Migration↑; Invasion↑; Cell spreading↑ HLA-1↑; TAP-1↑; TGF-β↓; FasL↓; VEGF-C↑
MCF10A Cell spreading↑
4T1 (m) Migration↑
PyVmT-CCR7 Proliferation→; Migration↑
CCL25 MDA-MB-231 Proliferation↑; Cisplatin-induced apoptosis↓; Migration↑; Invasion↑ MMP1/9/11/13↑ [48, 49]
MCF7 Migration→; Invasion→
CCR27 MDA-MB-231 Migration↑; Invasion↑ pErk↑; MMP7↑ [50]
CXCL1 MDA-MB-231 Migration↑; Invasion↑ Vimentin↑; E-cadherin↓; β-catenin↑; SOX4↑; pp65↑; pIκB↑; pErk↑; MMP2↑; MMP9↑ [4, 60, 61]
BT549
MCF-7 Vimentin↑; E-cadherin↓; β-catenin↑; SOX4↑; pp65↑; pIκB↑
T47D Migration→
ZR-75-1 Migration↑
BCSC-105/BCSC-608 Proliferation↑; Sphere Formation↑ CXCR7↑; TLR4↑; TNFSF10↑; CCL18↑; IL15↑; Twist1/2↑; CCL2↓; CCL28↓; CXCR4↓; SNAI2↓ [62]
Ab Proliferation↓; Sphere Formation↓
SUM149 KD Invasion↓ Fibronectin↓; N-cadherin↓; E-cadherin→; Vimentin→; pSTAT3↓; ALDH+ population↓ [58]
4T1 (m) Migration↑; Invasion↑ Vimentin↑; E-cadherin↓; N-cadherin↑; β-catenin↑; SOX4↑ [60]
PyMT cells Proliferation→ [63]
Ab MSC-CM induced Migration↓
CXCL2 SUM149 KD Invasion↓ Fibronectin↓; N-cadherin↓; E-cadherin→; Vimentin→; pSTAT3↓; ALDH+ population→ [58]
CXCL3 SUM149 KD Invasion↓ Fibronectin↓; N-cadherin↓; E-cadherin→; Vimentin→; pSTAT3↓; ALDH+ population→ [58]
MCF-7 Migration↑ [4]
T47D Migration→
ZR-75-1
CXCL4 MDA-MB-231 CXCL12-induced migration↓; CXCL12-CXCL4 heterodimerization [67]
CXCL447⁢–⁢70 Proliferation↓ [68]
CXCL5 PyMT cells Proliferation→ [63]
Ab MSC-CM induced Migration↓
CXCL7 MDA-MB-231 Migration↑; Invasion↑; Induction of CXCL7 in monocytes (co-culture) pFak↑; MMP13↑ [53]
MCF-7 Migration↑ VEGF↑ [4, 51, 52]
T47D Migration→
ZR-75-1 Migration→
MCF10A CXCL7; EV Invasion↑
CXCL8 Patient-derived BC cells Mammosphere formation↑ [4, 54, 55, 56, 57, 58]
MCF7/HER2-18 pHER2↑; pAkt↑; pErk↑
MDA-MB-231 Invasion↑, ↓ with Ab; Proliferation→
KD Proliferation↓; Migration↓; Invasion↓ Cyclin D1↓; p27↑; pAkt↓; integrin β3↓
SK-Br-3 Invasion↑, ↓ with Ab; Proliferation→
BT549 Invasion↑; Proliferation→
KD Proliferation↓; Migration↓; Invasion↓ Cyclin D1↓; p27↑; pAkt↓; integrin β3↓
BT20 Invasion↑
MCF-7 CXCL8; EV Migration↑; Chemoresistance↑
Ab Chemoresistance↓
T47D Migration→
ZR-75-1 Migration↑; Proliferation→
SUM149 KD Invasion↓ Fibronectin↓; N-cadherin↓; E-cadherin→; Vimentin↓; pSTAT3↓; ALDH+ population↓
CXCL9 MDA-MB-231 Migration↑ MMP9↑ [69, 70]
66.1 (m)
CXCL10 MDA-MB-231 Migration↑ ALDH1+ cells↑; pSTAT3↑; pErk↑; pCREB↑; pRhoA↑; pCdc42↑; MMP9↑ [70, 71]
MCF-7 [4]
T47D Migration→
ZR-75-1
66.1 (m) Migration↑ [69]
4T1 (m) p65↑; NF-κB activity↑ [72]
CXCL11 MDA-MB-231 Migration↑ ALDH1+ cells↑; pSTAT3↑; pErk↑; pCREB↑; MMP9↑ [70, 71]
MCF-7 Proliferation↓ [73]
66.1 (m) Migration↑ [69]
CXCL12 MDA-MB-231 Migration↑; Invasion↑→; Apoptosis↓; Colony↑ RhoA↑; Rac1↑; Cdc42→; BclX↑; Bmf↓; pAkt↑ [40, 43, 46, 75, 76, 77, 78, 79, 80, 81, 82]
EV Proliferation↑↓; Invasion↑; Apoptosis↑→; S & G2/M phase↑; Calcium flux↓
Ab Transendothelial migration↓
SUM-159 Migration↑ RhoA↑
MDA-MB-468 Migration↑ RhoA↑; Rac1↑; Cdc42→
MCF-7 Proliferation↑; Migration↑; Colony↑; Apoptosis↓; Adhesion↑; and invasion↑ [73, 78, 80, 83, 84, 85, 86, 87, 88]
KD; Ab Proliferation→; Transendothelial migration↓
SKBR3 Proliferation↑; Migration↑; Colony↑; Apoptosis↓; Adhesion↑; Invasion↑ pHER2↑; pEGFR↑; pErk↑
T47D Migration→
BT474/BT547 Migration→
SUM-149 Migration→
4T1 (m) Proliferation↑; Migration↑; Colony↑; Apoptosis↓; Adhesion↑; Invasion↑ pSTAT3↑; pErk↑
MVT1 (m) Migration↑
CXCL13 MDA-MB-231 CXCL13 ligand + CXCR5 EV Migration↑ Vimentin↑; Slug↑; Snail↑; N-cadherin↑; RANKL↑; E-cadherin→ in MDA-MB-231, ↓in T47D; MMP9↑; pSrc↑ [98]
T47D
MDA-MB-231 Ab Proliferation↓; Apoptosis↑ pErk↓; Cyclin D1↓; Caspase-9↑ [99]
CXCL14 MDA-MB-231 EV Proliferation↓; Invasion↓ [100]
CXCL16 MDA-MB-231 Migration↑; Invasion↑; F-actin polymerization↑ [101]
MCF-7
CXCL17 MDA-MB-231 KD Proliferation↓; Migration↓ [102]
SKBR3 Migration↓
MCF-7 pErk↑
CX3CL1 T47D Proliferation↑ pErk↑; pErbB1↑; pErbB2↑ [104]
XCR1 MDA-MB-231 EV Proliferation↓; Colony↓; Migration↑; Invasion↑ pErk↓; pJNK↓; pp38↓; Bid↓; pAkt↓; pmTOR↓; pP70S6K↓; p4EBP1↓; LC3↑ [3]
CCR2 MDA-MB-231 Antagonist Migration↑; Invasion↑ [19]
MCF-7
T47D
MCF10CA1d KO Growth↓; Mammosphere↓ ALDH activity↓ [20]
SUM225 EV CCL2-induced growth, invasion↑ E-cadherin↓; Twist1↑; CCL2-induced ALDH1A1↑; CCL2-reduced HTRA2↓; pErk↑; pSMAD3↓ [22]
DCIS.com KO CCL2-induced growth, invasion↓ PCNA↓; Caspase-3→; CCL2-reduced E-cadherin↑; CCL2-induced TWIST1↓; CCL2-induced ALDH1A1↓; CCL2-reduced HTRA2↑
CCR4 MDA-MB-231 EV Proliferation→; CCL17-induced migration↑ [32]
KD Proliferation→; CCL17-induced migration↓
CCR5 MDA-MB-231 EV Proliferation→ [5, 6, 7, 33]
Antagonist CCL5-inuced calcium flux↓, proliferation↓, glucose uptake↓, intracellular ATP/pyruvate/G6P↓; Proliferation↓; Colony formation↓; Migration↓ CCL5-induced pAkt↓, pmTOR↓, pGSK-3β↓; Arrest in the G1 phase
CCR5 EV MDA-MB-231 KD Migration↓ in hypoxia
MCF-7 Antagonist CCL5-inuced glucose uptake↓, proliferation↓, intracellular ATP↓
Hs578T CCL5-inuced calcium flux↓; Invasion↓
SUM-159 Invasion↓
CCR7 MDA-MB-231 Ab; KD Proliferation↓; Migration↓; Invasion↓; CCL19-induced; Apoptosis↑ VEGF-C↓; CCL21-induced pAkt/pErk↓ [38, 45, 46, 47]
MCF-7 CCL19 induced proliferation, migration & invasion↓
4T1 (m) Proliferation↓; Migration↓; Invasion↓ EpCAM↓; PVR↑
CCR9 MDA-MB-231 Ab CCL25-induced proliferation, migration, invasion↓ CCL25-induced MMP1/9/11/13↓ [48, 49]
CCR10 MDA-MB-231 KD CCL27-induced migration/invasion↓ CCL27-induced pErk and MMP7↓ [50]
CXCR1 SUM159 Ab; Antagonist Viability↓; Apoptosis↑ ALDH↓; FASL↑; pAkt↓; pFak↓ [59]
CXCR2 Patient-derived BC cells CXCR1/2 antagonist CXCL8-induced mammosphere formation↓ [56]
MCF7/HER2-18
MCF-7 EV Colony↑; Migration↑; Invasion↑ pAkt↑; E-cadherin↓; β-catenin↑; PI3K-P85α↓; Bax↓; Bak↓; Bad↓; Bid↑; Bcl2↑; Bcl-xL↑ [64]
BT474
SKBR3 KD Colony↓; Migration↓; Invasion↓ pAkt↓; E-cadherin↑; β-catenin↓; PI3K-P85α↑
MDA-MB-231 pAkt↓; β-catenin↓; PI3K-P85α↑; Bax↑; Bak↑; Bad↑; Bid↓; Bcl2↓; Bcl-xL↓
MCF10A-CXCL17 Inhibitor Invasion↓ VEGF↓ [51]
Cl66 (m) KD Proliferation→; Invasion↓; Paclitaxel/doxorubicin sensitivity↑; Paclitaxel/doxorubicin-induced apoptosis↑ [65, 66]
4T1 (m)
PyMT cells Proliferation→ [63]
AB; Inhibitor MSC-CM induced migration↓
CXCR3 MDA-MB-231 CXCR3B EV CSC population↑; tumorsphere↑ ALDH1+ cells↑; CD44+CD24−↑ [70, 71]
CXCR3B KD CSC population↓; tumorsphere↓ ALDH1+ cells↓; CD44+CD24−↓
Ab CXCL9/10/11-induced migration↓
66.1 (m) Antagonist AMG487; KD Proliferation→ [69]
4T1 (m) Proliferation→; Migration↓ p65↓; NF-κB activity↓ [72, 74]
CXCR4 MDA-MB-231 KD Proliferation↓; Migration↓; Invasion↓; Transendothelial migration↓; Apoptosis↑ [46, 75, 77, 78, 80, 89, 90]
Antagonist; Ab CXCL12-induced migration↓
MCF-7 Constitutively active CXCR4 Cadherin11↑; ZEB-1↑; E-cadherin↓; MMP-2↑ [83, 91, 92, 93]
KD; Ab; Antagonist Proliferation↓→; Transendothelial migration↓; Hypoxia-induced migration/invasion↓
MCF7 (TAM-R) Antagonist; KD Proliferation↓
BT-474 Ab CXCL12-induced invasion↓; Endothelial cell adhesion↓ [94]
MCF10A EV Invasion↑ pErbB2↑; pEGFR↑; pMet↑; pIGFRβ↑; MDM2↑; p53↑; E-cadherin↑; c-Myc↑; Survivin↑; Cyclin D1↑; p27↓ [95]
4T1 (m) KD Proliferation→ [96]
AMD3465 Migration↓ pSTAT3↓; pAkt↓; GSK-3↓; pJak2↓; cMyc↓ [97]
MVT1 (m) AMD3100 Migration↓ [87]
CXCR5 MDA-MB-231 CXCR5 Ab in CXCL13 ligand + CXCR5 EV cells Migration↓ Vimentin↓; Slug↓; Snail↓; N-cadherin↓; RANKL↓; E-cadherin ↑in T47D [98]
T47D
CXCR7 MDA-MB-231 EV Proliferation↑ [73]
MCF7 KD Proliferation↓; G0/G1↑; S-phase↓ Cyclin B1↓; Cdk4↓; p21↑; EGF-induced pErk↓; pEGFR↓
BT474 cells Proliferation↓
4T1 (m) KD/Inhibitor (CCX771) CXCL12-induced migration↓ pSTAT3↓; pErk↓; VCAM-1↓; MMP2↓; MMP9↓ [88]
CXCR8 4T1 (m) MCF7 CXCL17-induced pErk↓ [102]
CX3CR1 MDA-MB-436 EV pErk↑ [103]

BCSC, breast cancer stem cell; CM, conditioned media; CSC, cancer stem cells; EpCAM, epithelial cell adhesion molecule; ERO1-α, endoplasmic reticulum oxidoreductase; GSK-3β, glycogen synthase kinase 3β; HLA, human leukocyte antigen; HTRA2, HtrA serine peptidase 2; MMP, matrix metalloproteinase; MSC, mesenchymal stem cells; OPG, osteoprotegerin; PyMT, polyoma virus middle-T; RANKL, receptor activator of nuclear factor kappa-B ligand; TAP-1, transporter associated with antigen processing-1; uPA, urokinase plasminogen activator; VCAM-1, vascular cell-adhesion molecule-1; VEGF-C, vascular endothelial growth factor C; EV, expression vector; KO, knockout; KD, knockdown; HMGB1, high mobility group box 1; LC3B, light chain 3B; p27KIP1, cyclin-dependent kinase inhibitor 1B; pAkt, phosphorylated Akt; pmTOR, phosphorylated mammalian target of rapamycin; pErk, phosphorylated extracellular signal-regulated kinase; pSmad3, phosphorylated Smad3; GLUT-1, glucose transporter 1; BCL-2, B-cell lymphoma 2; BCL-xL, B-cell lymphoma-extra large; ALDH, aldehyde dehydrogenase; pPKCζ, phosphorylated protein kinase C zeta; ABCB1, ATP-binding cassette sub-family B member 1; TGF-β, transforming growth factor beta; FasL, Fas ligand; BclX, B-cell lymphoma-extra large; Bmf, Bcl-2 modifying factor; SOX4, SRY-box transcription factor 4; pIκB, phosphorylated inhibitor of kappa B; TLR4, toll-like receptor 4; CXCR7, C-X-C chemokine receptor type 7; TNFSF10, tumor necrosis factor (ligand) superfamily member 10; CCL18, C-C motif chemokine ligand 18; IL15, interleukin 15; SNAI2, snail family transcriptional repressor 2; pSTAT3, phosphorylated signal transducer and activator of transcription 3; MSC-CM, mesenchymal stem cell conditioned medium; pFak, phosphorylated focal adhesion kinase; pHER2, phosphorylated human epidermal growth factor receptor 2; pCREB, phosphorylated cAMP response element-binding protein; pRhoA, phosphorylated Ras homolog family member A; pCdc42, phosphorylated cell division control protein 42; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; pSrc, phosphorylated Src; pErbB1/2, phosphorylated Erb-B2 receptor tyrosine kinase 1/2; pJNK, phosphorylated c-Jun N-terminal kinase; pP70S6K, phosphorylated P70 ribosomal protein S6 kinase; p4EBP1, phosphorylated eukaryotic translation initiation factor 4E-binding protein 1; LC3, light chain 3; ALDH1A1, aldehyde dehydrogenase 1 family member A1; pSMAD3, phosphorylated Smad3; CCL2, C-C motif chemokine ligand 2; EpCAM, epithelial cell adhesion molecule; PVR, poliovirus receptor; FASL, Fas ligand; PI3K, phosphoinositide 3-kinase; CD44, cluster of differentiation 44; MDM2, mouse double minute 2 homolog; ↓ and ↑ indicate decrease and increase (p < 0.05 from statistical analysis), respectively, and → indicates no significant change.

Table 3. Roles of chemokines and chemokine receptors in animal models.
Chemokines Cell lines Species & model Treatment Function Signaling Immune contexture References
CCL2 MDA-MB-231 Female SCID; Orthotropic Ab Angiogenesis↓; Tumor growth↓; Metastasis↓ TAM↓ [26, 28, 111]
shCCL2
Intratumoral siCCL2 Tumor growth↓; Necrosis↑; Invasion↓; Angiogenesis→ PCNA↓; Caspase-3→; HMGB1↓; LC3B↑; ALDH1↓ M2 Mφ↓
TAM↑
FVB female mice; Lung metastasis Inflammatory Mo↑ [25]
MCF10CA1d Female athymic nude mice; Orthotropic CCL2 EV fibroblasts Tumor growth↑; Microvasculature↑; Metastasis→ [20]
CCL2 KO fibroblasts Tumor growth↓; Angiogenesis→ M2 Mφ↓; Neutrophil→
Ab Tumor growth→; Metastasis→; Angiogenesis→ Blood & tumoral CCL2↑ TAM→ [114]
A3250 SCID mice; Orthotopic KD Tumor growth↓; Metastasis↓; Necrosis↑ Lung & blood Mo↓; Splenic Mo→ [30]
MCF-7 Female athymic mice; Orthotropic Ab Tumor growth↓ [106]
Zebrafish embryos Cell dissemination↓
4T1 (m) Female mice; Orthotopic L-RNA aptamer inhibiting CCL2 Angiogenesis↓ TAM↓: less M2-like & more M1-phenotype [113]
KO mice Tumor growth↓→; Metastasis↓; Survival↑; Early tumoral necrosis; Angiogenesis↓ TAM↓; MDSCs↓ [144, 145]
Ab Tumor growth↓; Lung metastasis↓ [112]
Discontinued CCL2 Ab Metastasis↑; Survival↓; Angiogenesis↑ Ki67↑; VEGFA↑; pSTAT3↑ Metastatic & tumoral Mo↑ [115]
KD Bone/lung metastasis↑ [116]
Aerobic exercise Tumor growth↓ Plasma CCL2↓ [146]
XP265922 primary BC + CAF265922 cells Female NOD/SCID/IL2Rγ-null mice; co-transplant Fibroblast-specific CCL2 KD Tumor growth↓ NOTCH1↑ [16]
67NR (m) BALB/c mice; lung metastasis Intranasal CCL2 Tumor growth↑ CD45+ cells→; F4/80→; Ly6G→; CD11c→; CD19→; CD8→; CD4↑; M2 Mφ↑ [147]
Met-1 (m) Female nude mice; lung metastasis Ab Metastasis↓; Survival↑ Inflammatory Mo↓ [25]
AT-3 (m) C57BL/6 mice; Orthotopic KO mice Tumor growth↓; Pulmonary metastases↑; Splenomegaly↓; Splenic MDSCs↓; Tumoral MDSCs↓ [112]
Ab Tumor growth↓; Pulmonary metastases↓
PyMT tumor cells FVB/N mice; Orthotopic Ab Tumor growth↓; Angiogenesis↓ TAM↓ [106]
Spontaneous models Her2/neu-driven mammary carcinoma KO Survival↑; Tumor growth↓; Mobilization of endothelial precursor cells↓ [27]
CCL3 MDA-MB-231 Nude mice; Orthotropic KO Mo Tumor growth→; Metastasis↓ [105]
E0771 (m) Mice; Orthotropic Metastasis↓ Mφ↓; Blood Mo↑; Myeloid cells↓
Met-1 (m) FVB mice; Orthotropic Ab Metastasis↓
CCL4 D2F2/E2 tumors (m) s.c. pDNA-CCL4 vaccination Tumor growth↑; Tumor rate↑ [121]
CCL5 MCF-7 Zebrafish embryos Ab Cell dissemination↓ [106, 107]
PyMT tumor cells FVB/N mice; Orthotopic Ab; KO mice Tumor growth↓; Metastasis↓; Angiogenesis↓; Survival↑; CTC↓ TAM↓; CD45→; CD4↓
4T1 (m) Female mice; Orthotopic Aerobic exercise Tumor growth↓ Plasma CCL5↓ [146]
Ab; KO mice Tumor growth↓; Metastasis↓ CD4→; CD8→; NKT→; Treg↓; TAM→; Impaired MDSCs [108]
KD Tumor growth↓→ Mφ↓; Lymphocytes↑; CD4↑; CD8↑ [12]
SCID mice Tumor growth↓
410.4 (m) Antagonist Met-CCL5 Tumor growth↓; Necrosis↑ Mφ↓ [148]
TAN primary tumor cells TAN mice; Orthotopic Primary tumor growth→; Tumor recurrence↑ Mφ↑ in residual tumors; CD4 & CD8↓ in recurrent tumors [109]
CCL8 MDA-MB-231 Nude mice; s.c. Ab Invasion↓; Seeding↓ [13, 110]
MCF10.DCIS SCID mice; Orthotopic KO mice Delay in the latency for tumor onset M2 Mφ↓
E0771 (m) Female mice; s.c. Ab; KO mice Survival↑ Vimentin↓ TAM↓
CCL17 4T1 (m) Orthotopic Chemotoxin Lung metastasis↓ [120]
TARC-PE38
CCL18 MDA-MB-231 SCID mice; Orthotopic Intratumoral injection Angiogenesis↑; Lung/liver metastasis↑; Vascular invasion↑; Lung weight↑ [34, 122]
BT-474
CCL20 MDA-MB-231 Nude mice; Cardiac Ab Metastasis↓; Bone metastasis↓ [35]
Nude mice; Orthotropic EV Tumor growth↑ [36]
CCL21 SKBR-3 Nude mice; s.c. CCL21 + human lymphocytes (i.v.) Tumor growth↓; Survival↑ [42]
MCF7
4T1 (m) Mut-CCL21 Tumor growth→; Lymph nodes↓ [41]
CCL27 4T1 (m) Orthotropic CCL27-PE38 Lung metastasis→ [120]
CXCL1 MDA-MB-231 SCID mice, Orthotropic THP1-M2 or THP1-M2/shCXCL1 cells Tumor growth & lung metastasis: ↑ in THP1-M2 & ↓ in THP1-M2/shCXCL1 Vimentin↑, E-cadherin↓, SOX4↑, p-p65↑ in THP1-M2; Vimentin↓; E-cadherin↑; SOX4↓; pp65↓ in THP1-M2/shCXCL1 [60]
Chemokinostatin-1 Tumor growth↓; Angiogenesis↓ [123]
PyMT mammary cancer cells MMTV-PyMT+/- mice TAM-shCXCL1, shCXCL1/2 Tumor growth↓; Lung metastasis↓ CD11b(+)Gr1(+) myeloid cells↓ [60, 124]
CXCL4 MDA-MB-231 SCID mice; s.c. CXCL447⁢–⁢70 Tumor growth↓ Tumoral mRNA levels: F4/80↑, CD11c↑, IFN-γ↑ [68]
CXCL7 MDA-MB-231 SCID mice; Orthotropic Ab Tumor growth↓; Lung metastasis↓ M2 Mφ↓ [53]
CXCL8 MDA-MB-231 Nude mice; s.c. Angiogenesis↑ [54]
SK-BR3
CXCL9 4T1 (m) Balb/c mice; Orthotropic Ab Tumor growth↑ [126]
CXCL12 Human BC PDX HER2>TNBC=LA in tumor growth [127]
MDA-MB-231 Lung metastasis EV Lung metastasis↓; Survival↑ [81, 128]
Orthotropic Tumor growth↑
Ab Lymphatic vessel↓; Lymph node metastasis↓
MCF-7 SCID; Orthotopic ICI-inhibited tumor growth↑ [131]
Ab Tumor growth→, ↓ in CAF-induced tumors; Angiogenesis→, ↓ in CAF-induced tumors [83]
MVT1 (m) Fibroblast CXCL12 cKO mice; Orthotopic Tumor growth↓; Lung metastasis↓; Survival↑; Angiogenesis↓ [87]
Lung metastasis Lung metastasis→
4T1 (m) Female mice; Orthotopic WT compared to mutant EV Tumor growth↓; Lung metastasis↓; Angiogenesis→ DC in lymph nodes↑; Splenic MDSC↓ [129, 130]
CXCL12-EV stromal cells Lung metastasis↓
MTLn3 (r) SCID mice; Orthotopic EV Tumor growth→; Invasion↑; Angiogenesis↑ TAM↑ [132]
CXCL14 MDA-MB-231 SCID mice; Orthotopic EV Tumor growth↓; Lung metastasis↓; Angiogenesis↓ [100]
4T1 (m) Female Balb/c mice; Orthotopic EV Tumor growth↓; Lung metastasis↓ Myeloid cells↓, Treg↓, CD8+↑ in primary tumors; TAM↓, Treg↓, CD8+↑ in lung metastatic tumors [140]
CXCL17 4T1 (m) Female Balb/c mice; Orthotopic EV Tumor growth↑ [102]
CX3CL1 Tg-neu mice Intratumoral injections of Ad-CX3CL1 Palpable tumors↑; Angiogenesis→ [104]
KO in Tg-neu mice Delayed mammary tumor onset; Tumor number↓; Tumor growth→
KO in Tg-PyMT mice Mammary tumor onset→; Tumor number→; Tumor growth→
XCR1 MDA-MB-231 EV Tumor growth↓ [3]
CCR1 E0771 (m) Mice; Orthotropic KO Mo Metastasis↓ Mφ↓; Myeloid cells↓ [105]
CCR2 SUM225 Female NOD/SCID EV Invasion↑ Ki67↑; Caspase-3↓; ALDH1A1↑; HTRA2↓ CCL2+ fibroblasts↑ [118]
MCF10CA1d Female athymic nude mice; Orthotropic KO Tumor growth↓ M2 Mφ↓ [20]
MCF-7 Antagonist E2-induced tumor growth, Angiogenesis, Metastasis↓ PCNA↓ [19]
hDCIS cells NOD-SCID IL-2rγ−/− mice CCR2+ cells Tumor formation↑ PCNA↑; pSamd3↑; pErk↑ [117]
KD Tumor growth↓ PCNA↓; Caspase-3↑; ALDH1A1↓; HTRA2↑ [118]
4T1 (m) Female mice; Orthotopic KD Tumor growth↓; Metastasis→ M2 Mφ↓ [20]
Aerobic exercise Tumor growth↓ Plasma CCR2↓ [146]
PyVmT mammary carcinoma cells FVB mice; Intraductal injection KD Tumor growth↓; Angiogenesis↓ PCNA↓; Caspase-3→ F4/80+ Mφ↓; M2 Mφ↓; F4/80+CCR2+ Mφ→; CD8+↑; CD4+→ [31]
E0771 (m) Female CCR2 KO mice KO mice Tumor growth↓; Progression-free survival↑ CD4↑; CD8→; TIM↓; TIN↑ [119]
Mice; Orthotropic KO Mo Metastasis↓ Mφ↓; Blood Mo↑ [105]
AT-3 (m) C57BL/6 mice; Orthotopic KO mice Tumor growth↓; Pulmonary metastases↑; Splenomegaly↓ Splenic MDSCs↓; Tumoral MDSCs↓ [112]
Spontaneous models Her2/neu-driven mammary carcinoma KO Survival↓; Tumor growth↑; mobilization of endothelial precursor cells↑ [27]
Antagonist CCX872
CCR4 MDA-MB-231 Nude mice; Orthotropic EV Tumor growth↑; Lung metastasis↑; Angiogenesis↑ [32]
KD Tumor growth↓; Lung metastasis↓; Angiogenesis↓
CCR5 MDA-MB-231 SCID mice; lung metastasis Antagonist maraviroc The number and the size of pulmonary metastases↓; Tumor growth→in established tumors [5]
Nude rats Bone metastasis↓ [33]
4T1 (m) Female mice; Orthotopic Aerobic exercise Tumor growth↓ Plasma CCR5→ [146]
CCR7 PyVmT-CCR7 FVB mice; Orthotopic Compared to CCR7 negative cells Tumor growth↑; Lymph node metastasis↑; Lung metastasis↓ Survival→ [39]
4T1 (m) Female mice; Orthotopic KD Tumor growth↓; Metastasis↓ [47]
CXCR1 SUM159 SCID mice; Orthotopic Antagonist Tumor growth↓; CD44+CD24–(CSC) cells↓; metastasis↓ ALDH↓; pAkt↓; pFak↓ [59]
MDA-MB-453 Tumor growth↓; Metastasis→
HCC1954 Tumor growth↓; Metastasis↓
CXCR2 MDA-MB-231 Female mice; Orthotopic KD Tumor growth↓; Metastasis↓; Chemoresistance↓ [64]
PyMT mice KO mice Tumor growth↑; Metastasis↑ Killing ability of Cxcr2 KO TANs↓ TAN↑; TAM↓ [125]
Cl66 (m) Female mice; Orthotopic KD Tumor growth→; Metastasis↓→; Angiogenesis↓; Paclitaxel-reduced tumor growth, metastasis, angiogenesis↓ PCNA→; Caspase-3↑ [65, 66]
CXCR3 MDA-MB-231 Lung metastasis Antagonist Metastasis↓ [71]
66.1 (m) Lung metastasis (Antagonist-treated cells); Orthotopic Antagonist AMG487 Tumor growth→; Metastasis↓; Metastasis↑ in NK cell-depleted mice [69]
4T1 (m) Orthotopic; Lung metastasis Antagonist; KD; KO mice Tumor growth→; Metastasis↓ Splenic CD3/CD4/CD8↑ [74]
CXCR4 Human BC HER2 BC PDX Inhibitors: AMD3100; TN14003 Tumor growth↓; Metastasis↓; Angiogenesis↓ Ki-67→; Caspase-3→ [127]
TNBC PDX Tumor growth→; Metastasis→; Angiogenesis→ Ki-67→
MDA-MB-231 SCID mice; lung metastasis CXCR4 Ab; KD; Inhibitors Metastasis↓; Lung weight↓ [43, 77, 89, 134]
SCID mice; Orthotopic KD; AMD3100; CTCE-9908 Tumor growth↓→; Metastasis↓ Ki-67↓ in lung metastasis [78, 90, 135, 136]
MTLn3 SCID mice; Orthotopic; EV Invasion↑; Metastasis→ VEGFA→ [133]
MCF-7 Female SCID mice; Orthotopic EV Tumor growth↑; Metastasis↑; lymphatic invasion↑ E-cadherin↓; ZO1→ [91, 131]
KD/Ab/AMD3100 Tumor growth→, ↓ in CAF cotreatment; Metastasis↓ [83, 93]
MCF7 (TAM-R) AMD3100 Tumor growth↓ ABCG2↓
4T1 (m) Orthotopic; Lung metastasis KD Tumor growth↓; Metastasis↓; Angiogenesis→; Survival→ [96]
Orthotopic Vaccinia viruses Tumor growth↓; Metastasis↓ CD31↓; Ki67↓; VEGF↓ Bone marrow-derived endothelial and myeloid cells ↓; Survival↑ [139]
Orthotopic Inhibitors Tumor growth↓; Metastasis↓; Survival→; Apoptosis↑ pAkt↓; pErk↓; pFak↓; Bcl-2↓; Bax↑; Caspase-3↑ TAM↓ [85, 97, 137]
E0771 (m) Orthotopic AMD3100 Metastasis↓; Survival→ CD8→; Treg↓
MMTV-PyMT Inhibitor: CTCE-9908 Tumor growth↓; Metastasis→ VEGF↓ [138]
CXCR6 4T1 (m) Mice; s.c.; Orthotopic KO mice Tumor growth→; Radiation-reduced tumor growth↑ [141]
CXCR7 MTLn3 SCID mice; Orthotopic EV Invasion→; Metastasis↓ VEGFA↑ [133]
MDA-MB-435 SCID mice; Orthotopic EV Tumor growth↑ [88, 130, 142]
4T1 (m) Mice; s.c.; Orthotopic KD/Inhibitor (CCX771) Tumor growth↓→; Metastasis↓ pSTAT3↓; pErk↓; CD31↓; Ki67↓; Cyclin D1↓; MMP9↓ TAM↓
AT-3-FL (m) Orthotopic; Lung metastasis Endothelial CXCR7 cKO Tumor growth↑; Metastasis↑; Angiogenesis→; Survival↓ [143]
E0771 (m)
CX3CR1 MDA-MB-231 SCID mice; Intracardiac KO mice Bone metastasis↓ [103]
MDA-MB-436 EV Bone metastasis↑

Ab, antibody; ALDH1, aldehyde dehydrogenase 1; CAF, carcinoma-associated fibroblasts; CTC, circulating tumor cells; EV, expression vector; hDCIS, human ductal carcinoma in situ; HTRA2, high temperature requirement protein A2; ICI, ICI182780; KD, knockdown; KO, knockout; m, mouse; MDSC, myeloid-derived suppressor cells; Mo, monocytes; PCNA, proliferating cell nuclear antigen; PDX, patient-derived xenografts; TAM, tumor-associated macrophages; TAN, tumor-associated neutrophils; TARC-PE38, TARC fusion with a truncated toxin PE38; TIM, tumor-infiltrating Mφ; TIN, tumor-infiltrating neutrophils; SCID, severe combined immunodeficiency; shCCL2, short hairpin C-C motif chemokine ligand 2; siCCL2, small interfering C-C motif chemokine ligand 2; FVB, Friend virus B; L-RNA, long RNA; NKT, natural killer T cells; THP1-M2, THP-1 macrophage cell line (M2 polarized); shCXCL, short hairpin C-X-C motif chemokine ligand; IFN-γ, interferon gamma; HER2, human epidermal growth factor receptor 2; TNBC, triple-negative breast cancer; LA, luminal A; ICI, immune checkpoint inhibitor; DC, dendritic cell. ↓ and ↑ indicate decrease and increase (p < 0.05 from statistical analysis), respectively, and → indicates no significant change.

Table 4. Roles of chemokines and chemokine receptors in human breast cancers.
Chemokines Biomarker Clinical correlation Immune contexture Prognosis Overall survival References
CCL1 Invasive; ER- Grade Treg↑ ↓ [168, 175]
CCL2 BC; Low differentiation; Invasive ductal BC; Early relapse; ER-; PR-; CAFs; BL; Claudin-low; LB; Advanced Postmenopausal; Lymph node involvement; Grade; Tumor size; Nodal status; Angiogenic; AP-1+; Ki67↑ TAM↑→; CD3↑; CD20↑; CD68↑ X in stromal CCL2 ↓ in both tumoral & stromal CCL2; BL>HER2>LB>LA [14, 17, 23, 111, 117, 150, 153, 159, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172]
CCL3 BC; Inflammatory BC; ER-; PR- Grade; Ki67↑ ↑; ↓ in non-TNBC [149, 150, 151, 152, 153, 154]
CCL4 Inflammatory BC; ER-; Metastasis of LB Grade; Ki67↑ ↑ [149, 151, 153, 155, 157, 176]
CCL5 TNBC; Advanced; Inflammatory BC; BL; HER2; ER-; PR- Stage; Histological grade; LN+; Microvessel density CD163+ Mφ infiltration O in BC, LA, LB ↑; ↓ in HER2 BC [5, 8, 9, 107, 152, 155, 156, 157, 158, 247, 248]
CCL7 BC; Poorly differentiated; TNBC; AA Grade; Ki67↑ ↓ [153, 157, 159]
CCL8 TNBC; AA; ER- Grade; Ki67↑ X ↓, EA [13, 153, 157]
CCL11 HER2 O [157]
CCL13 HER2 Ki67↑ [153]
CCL14 O ↑ [155, 160]
CCL15 O ↑ [151]
CCL16 X in LA; O in TNBC [156]
CCL17 TNBC; AA Ki67↑ X ↓, AA [151, 153, 157]
CCL18 BC, Advanced stage; Metastatic BC Lymph node metastasis X ↓, with higher CCL18-positive TAM [34, 151, 159, 168]
CCL19 Aggressive O; X in LA ↑, ER+ (plasma levels); ↓ in ER+ (tumoral levels) [151, 155, 156, 157, 173, 178]
CCL20 TNBC; AA; ER- Ki67↑ ↓ [35, 36, 153, 157]
CCL21 Metastatic BC O ↑ [151, 155, 157, 160, 173, 179]
CCL22 BC; HER2 Low grade O ↑; → [151, 155, 157, 159, 175]
CCL23 Grade O [153, 157]
CCL24 ↓ [151, 155]
CCL25 TNBC; AA ↓; AA [157]
CCL26 Inflammatory BC [149]
CCL27
CXCL1 BC; TNBC; ER-; Metastasis of BC Grade, in stromal CXCL1; Ki67↑ CD133↑ (Stem cell marker); CD68↑ (Mφ) X, in stromal CXCL1 ↑; ↓; → [62, 153, 188, 201, 202, 203, 204]
CXCL2 Metastasis of BC O ↑ [187, 188, 190, 203]
CXCL3 Aggressive BC; Metastasis of BC X ↑; ↓; → [187, 188, 189, 190, 203, 205]
CXCL5 BC; ER- Low metastasis in BC, LB → [153, 161, 168, 176, 188]
CXCL6 ER-; Metastasis of BC ↑; → [187, 188]
CXCL7 Stage III ↑; →; ↓ [53, 155, 187, 189, 190]
CXCL8 BC; Inflammatory BC; TNBC; Advanced stage; LA; LB; ER-; HER2+; PR-; CAFs; ER- Lymph node metastasis Angiogenic; Grade; Stage; AP-1+; Ki67↑ CD68↑ X ↓; ↓ in CXCL8 (-251) A allele [149, 150, 153, 155, 159, 166, 176, 187, 188, 189, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200]
CXCL9 BC, TNBC, Low proliferative, Lymph node negative; HER2; ER- Grade; Ki67↑ O ↑, TNBC, luminal HER2; ↓ [153, 155, 159, 160, 187, 189, 190, 203, 209]
CXCL10 BC, Poor differentiation; HER2; ER-; HR- Stage; Grade; Ki67↑ TIL↑ O → [153, 159, 187, 190, 203, 210, 211, 212]
CXCL11 BC, TNBC; HER2; ER- Grade; Ki67↑ → [153, 159, 203]
CXCL12 BC, BL; Subtypes→ Stage; Grade; lymph node metastasis Treg↑ O ↑, High plasma levels, CXCL12δ isoform; → [82, 155, 160, 168, 187, 189, 190, 203, 216, 217, 218, 219, 220, 221, 222]
CXCL13 BC; ER-; Metastatic BC Lymph node metastasis with CXCR5 coexpression; Ki67↑ O ↑→ [52, 98, 155, 160, 168, 187, 189, 190, 203, 209]
CXCL14 Lymph node metastasis↓ ↑, BL, HER2, LA [100, 140, 155, 187, 189]
CXCL16 Stage in N-terminal CXCL16 X in HER2 [101, 156]
CXCL17 ER- Ki67↑ ↓ [102, 153]
CX3CL1 Inflammatory BC; LB Grade; Stage; Tumor size; Lymph node metastasis; PR+; Ki67↑ Stromal CD8↑; Intratumoral DC↑; Stromal NK↑; TIL↑ ↑; ↓ [149, 153, 245, 246]
CCR2 Invasive ductal BC ↑ [117, 173, 174]
CCR4 Lymph node metastasis; HER2 expression ↑; ↓ [32, 173]
CCR5 BL; HER2 [5]
CCR6 Pleura metastasis; Aggressive → [177, 178]
CCR7 BC; Metastatic BC; HER2+; TNBC; LB Lymph node metastases↑→; Recurrence↑→; TNM stage; Grade; Invasion; Aggressive CD68↑; FOXP3↑; CD8→; CD20→ ↑, HER2, BL; ↓; → [43, 44, 47, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186]
CCR9 Poorly differentiated [49]
CCR10 Capsular invasion; Stage; Lymph node metastases [50]
CXCR1 Invasive BC [174]
CXCR2 High-grade; TNBC; ER-; PR-; Relapse↓; Invasive BC TILs↑; CD3↑; CD8↑; PD-L1↑; Infiltration of T/B cells X in C1208T variation ↑; ↓; ↓ in CXCR2 (+1208) T allele [64, 174, 200, 206, 207, 208]
CXCR3 ER- Grade; Tumor size ↑, BL, ER-, LN+; ↓ [74, 213, 214, 215]
CXCR4 BC; LA; LB; BL; HER2; Locally advanced BC; TNBC; Atypical ductal hyperplasia; Ductal carcinoma in situ; Invasive BC Metastasis of lymph node & liver; Distant metastasis; Recurrence in HER2-, TNBC; Grade; ER-; PR-; tumor size & advanced TNM stage in TNBC CXCR4+ Treg↑ (BL>Luminal) ↑, high levels in fibroblasts, BL, ER-; ↓, TNBC; →; Unmethylated CXCR4: hypermethylated CXCL12/unmethylated CXCR4↓ [43, 94, 131, 174, 177, 181, 182, 185, 213, 214, 216, 217, 218, 219, 221, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243]
CXCR5 Lymph node metastasis; Stage [199]
CXCR6 Stage [101]
CXCR7 ER-; PR-; TNBC; ER+; PR+ TNM stage; Grade ↓ [88, 218, 244]
CXCR8 Grade; Ki67↑ → [102]
CX3CR1 Brain metastasis → [177]

O, good; X, Poor; AA, African Americans; CAFs, cancer-associated fibroblasts; EA, European Americans; ER-BC, ER-negative breast cancer; PD-1, programmed cell death 1; TILs, tumor-infiltrating lymphocytes; BL, Basal-like; HER2, Human epidermal growth factor receptor 2; LB, Luminal B; LA, Luminal A; ER, Estrogen receptor; PR, Progesterone receptor; TNBC, Triple-negative breast cancer; LN+, Lymph node positive; NK, Natural killer cells; FOXP3, Forkhead box P3; TNM, Tumor-node-metasta. ↓ and ↑ indicate decrease and increase (p < 0.05 from statistical analysis), respectively, and → indicates no significant change.

2. The XCL-XCR Axis
The XCL1/2-XCR1 Axis

Studies on the XCL1/2 in cell lines and animal models and human breast cancer samples are lacking. The XCR1 overexpression in MDA-MB-231 cells reduced cell proliferation and colony formation but increased migration and invasion. The XCR1-mediated signaling shows reduced phosphorylated extracellular signal-regulated kinase (pErk), phosphorylated Jun N-terminal kinase (pJNK), phosphorylated p38 (pp38), BH3-interacting domain death agonist (Bid), phosphorylated protein kinase B (pAkt), phosphorylated mammalian target of rapamycin (pmTOR), phosphorylated p70 ribosomal S6 kinase (pP70S6K), and phosphorylated eukaryotic translation initiation factor 4E binding protein 1 (p4EBP1) but induced microtubule-associated protein 1A/1B-light chain 3 (LC3) (Table 2) [3]. Animal models bearing XCR1-expressed breast cancer cells reduced tumor growth (Table 3) [3]. Although studies on XCR1 in patients with breast cancer are lacking, the XCL1/2-XCR1 axis shows a benefit for breast cancer, probably reducing tumor growth.

3. The CCL-CCR Axis
3.1 The CCL3/5/7/8/14/15/16/23-CCR1 Axis

CCL3 induced migration in MCF-7 and ZR-75-1 cells but did not change the migration of T47D cells (Table 2) [4], probably depending on cellular expression levels of CCR1. Blocking CCL3 reduced metastasis and treatment of CCL3 KO monocytes also decreased metastasis but caused no change in tumor growth, reducing infiltration of Mφ and myeloid cells (Table 3) [105]. In human breast cancer samples, 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 shows the increased Ki67 (Table 4). A good survival of CCL3 is reported but non-triple-negative breast cancer (TNBC) has a poor survival (Table 4) [149, 150, 151, 152, 153, 154]. In MDA-MB-231 and MCF-7 cells, CCL5 increased proliferation, calcium flux, migration, invasion, glucose uptake, glycolysis, and intracellular ATP/pyruvate/G6P, showing activation of Akt, mTOR, GSK-3β and increased glucose transporter protein 1 (GLUT-1) levels (Table 2) [5, 6, 7]. However, CCL5 had no effects on migration of T47D and ZR-75-1 cells but reduced tamoxifen-induced cell death. In trastuzumab- and tamoxifen-resistant cells, knockdown (KD) of CCL5 decreased chemoresistance [8] and reduced phosphorylated Signal transducer and activator of transcription 3 (pSTAT3), B-cell lymphoma 2 (BCL-2) and B-cell lymphoma-extra large (BCL-xL) with increased poly (ADP-ribose) polymerase (PARP) and caspase-9 activity but had no effect on proliferation of 4T1 cells (Table 2) [4, 6, 9, 10, 11]. CCL5 antibody (Ab) and CCL5 KO mice showed decreased tumor growth, metastasis, and angiogenesis, increasing survival (Table 3) [12, 106, 107, 108]. In addition, CCL5 Ab and KO showed reduced tumor-associated macrophages (TAM) and CD4 but no change in CD45 cells in tumors of mice bearing PyMT tumor cells [106, 107], but had no change in CD4, CD8, natural killer T cells (NKT), and TAM with decreased Treg and impaired myeloid-derived suppressor cells (MDSCs) in tumors of mice bearing 4T1 cells [108]. On the other hand, tumors of mice bearing CCL5 KD 4T1 cells had decreased Mφ infiltration and increased CD4 and CD8 lymphocytes (Table 3) [12]. In addition, CCL5 had no effect on primary tumor growth but increased tumor recurrence by increasing Mφ infiltration in residual tumors and decreasing CD4 and CD8 cell infiltration in recurrent tumors (Table 3) [109]. In human breast cancer samples, CCL5 reduced risks of breast cancer and LA/LB subtypes and had a good prognosis and survival although a poor survival in the HER2 subtype was reported (Table 4). CCL5 increased microvessel density and CD163+ Mφ infiltration (Table 4) [5, 8, 9, 107, 152, 155, 156, 157, 158, 247, 248]. Studies on CCL7 for breast cancers in cell and animal models are lacking. CCL7 is highly expressed in breast cancers, poorly differentiated cancers, TNBC, and African Americans. Expression levels of CCL7 are related to tumor grade and shows an increased Ki67, showing a poor survival (Table 2) [153, 157, 159]. CCL8 induced cell migration in cell lines (Table 2) [13] but CCL8 Ab and KO mice decreased tumor invasion and seeding, delayed the latency for tumor onset, reduced vimentin and M2-Mφ and TAM infiltration in tumors, resulting in a better survival (Table 3) [13, 110]. CCL8 shows a 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 shows the increased Ki67 (Table 4) [13, 153, 157]. CCL14 is reported as an indicator for a good survival and prognosis (Table 4) [155, 160]. CCL15 is reported as an indicator for a good survival and prognosis (Table 4) [151]. CCL16 shows an increased risk in LA subtype and a decreased risk in TNBC (Table 4) [156]. Expression levels of CCL23 are related to tumor grade and good prognosis (Table 4) [153, 157]. Studies on CCL14, CCL15, CCL16, and CCL23 for breast cancers in cell and animal models are lacking. Treatment of CCR1 KO monocytes in animal models decreased metastasis and reduced Mφ and myeloid cell infiltration in tumors (Table 4) [105]. Studies on CCR1 in cell models and patients with breast cancer are lacking.

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

In cell models (Table 2), CCL2 increased mammosphere, cell viability, migration, invasion, and G2/M phase in cell cycle and decreased apoptosis in parallel with increased β-catenin, vimentin, matrix metalloproteinase 9 (MMP9), endoplasmic reticulum oxidoreductin 1 alpha (ERO1-α), twist family bHLH transcription factor 1 (TWIST1), NOTCH, proliferating cell nuclear antigen (PCNA), phosphorylated Akt (Protein Kinase B) (pAkt), phosphorylated mammalian target of rapamycin (pmTOR), phosphorylated extracellular signal-regulated kinase (pErk), phosphorylated Smad3 (pSmad3), vascular endothelial growth factor (VEGF), and Ras homolog family member A (RhoA), and decreased caspase-3, cyclin-dependent kinase inhibitor 1B (p27KIP1), and E-cadherin [4, 14, 15, 16, 17, 18, 19, 20, 21, 22]. However, SUM225 cells had no change in cell growth and invasion. Similarly, T47D cells were changed in migration [22]. On the other hand, CCL2 Ab and KD decreased mammosphere, cell viability, migration, and invasion and increased apoptosis, necrosis, and autophagy in parallel with decreased MMP9, vimentin, N-cadherin, Ki67, high mobility group box 1 (HMGB1), and increased light chain 3B (LC3B) [14, 15, 23, 24, 25]. Interestingly, CCL2 Ab and KD in MDA-MB-231 cells had no effects on proliferation and decreased apoptosis with decreased caspase-3 and increased NOTCH [16, 18, 24, 26, 27, 28, 29]. Also, CCL2 KD in A3250 cells had no change in proliferation and colony formation [30]. CCL2 KD in Polyoma virus middle T antigen-transformed (PyVmT) carcinoma cells showed increased necrosis and autophagy and decreased viability, migration, angiogenesis, and Mφ recruitment with decreased caspase-3 and Ki67 [23, 31]. In animal cancer models (Table 3), CCL2 Ab and KD reduced angiogenesis, tumor growth, and metastasis, and enhanced necrosis in parallel with decreased TAM infiltration, PCNA, HMGB1, and aldehyde dehydrogenase 1 (ALDH1) and increased LC3B [25, 26, 28, 30, 106, 111, 112, 113]. CCL2 expression vector (EV) fibroblasts induced tumor growth and microvasculature but had no change in metastasis, while CCL2 KO fibroblasts reduced tumor growth but had no change in angiogenesis with decreased M2 Mφ [20]. However, CCL2 Ab against MCF10CA1d cells had no effects on tumor growth, metastasis, angiogenesis, and TAM infiltration [114]. Discontinuation of CCL2 Ab increased metastasis and angiogenesis, resulting in a shorter survival, in parallel with increased Ki67, VEGF, pSTAT3, and metastatic and tumoral Mo infiltration [115]. On the other hand, CCL2 KD in 4T1 cells was reported to increase bone and lung metastasis [116] and CCL2 KO mice bearing AT-3 cells reduced tumor growth but increased pulmonary metastasis with decreased splenic and tumoral MDSCs [112]. In human breast cancer samples (Table 4), CCL2 shows a poor survival in both tumoral and stromal CCL2 positive cancers with the worse survival order of Basal-like (BL)>Human epidermal growth factor receptor 2 (HER2)>Luminal B (LB)>Luminal A (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, CD68 infiltration with increased or unchanged TAM in tumors [14, 17, 23, 111, 117, 150, 153, 159, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172]. CCL7, CCL8, and CCL16 are described in the section of the CCL3/5/7/8/14/15/16/23-CCR1 axis. CCL13 is highly expressed in HER2 subtype and shows the increased Ki67 (Table 4) [153]. Further studies on CCL13 in cell and animal models require to clarify roles of CCL13 in breast cancer. Although CCR2 antagonist increased cell migration and invasion [19], CCR2 KO in cell models decreased CCL2-induced growth, invasion, TWIST1, aldehyde dehydrogenase 1 family member A1 (ALDH1A1), and PCNA, increased CCL2-reduced E-cadherin and HTRA2, and had no change in caspase-3 (Table 2) [20, 22]. In animal models (Table 3), CCR2 expressing cells showed increased tumor growth and invasion with induced CCL2 positive fibroblasts, showing increased Ki67, PCNA, and ALDH1A1, activated Smad and extracellular signal-regulated kinase (Erk), and decreased caspase-3 and HTRA2 [117, 118]. On the other hand, CCR2 KO, KD, and antagonist reduced tumor growth, metastasis, and angiogenesis with decreased M2 Mφ and neutrophile infiltration, showing decreased PCNA and ALDH1A1 and increased caspase-3 and HTRA2 [19, 20, 31, 118, 119]. However, CCR2 KO mice bearing AT-3 cells showed decreased tumor growth and increased pulmonary metastasis, reducing splenic and tumoral MDSCs [112]. Interestingly, spontaneous models of CCR2 KO mice bearing Her2/neu-driven mammary carcinoma increased tumor growth and mobilization of endothelial precursor cells, resulting in a shorter survival [27]. CCR2 is highly expressed in invasive ductal breast cancer and shows a good survival (Table 4) [117, 173, 174].

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. Studies on CCL11, CCL24, CCL26, and CCL28 in cell and animal models for breast cancer are lacking. CCL11 is highly expressed in HER2 subtype and shows a good prognosis (Table 4) [157]. CCL24 shows a poor survival in patients with breast cancer (Table 4) [151, 155]. CCL26 is highly expressed in inflammatory breast cancers (Table 4) [149]. Studies on CCL28 and CCR3 in cell and animal models for breast cancer and patients with breast cancer are lacking.

3.4 The CCL17/22-CCR4 Axis

Studies on CCL17 in cell models for breast cancer are lacking and chemotoxin TARC-PE38 for CCL17 reduced lung metastasis in animal models (Table 3) [120]. CCL17 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 (Table 4) [151, 153, 157]. Studies on CCL22 in cell and animal models for breast cancer are lacking. 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 (Table 4) [151, 155, 157, 159, 175]. In cell models, CCR4 expression increased CCL17-induced migration with no change in proliferation, while CCR4 KD decreased CCL17-induced migration with no change in proliferation (Table 2) [32]. In animal models, CCR4 overexpression increased tumor growth, lung metastasis, and angiogenesis, while CCR4 KD decreased these effects (Table 3) [32]. CCR4 has controversial survival effects between patients with breast cancer. Expression levels of CCR4 are related to lymph node metastasis and HER2 expression (Table 4) [32, 173]. A clinical trial (NCT06320392) is designed to explore whether CCR4-NOT Complex Subunit 7 contributes to metastasis in metastatic BC patients through NK cell resistance (https://clinicaltrials.gov/search?cond=breast%20cancer&intr=ccr4).

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 induced migration in MCF-7 and ZR-75-1 cells but had no effects on migration in T47D cells (Table 2) [4], probably depending on cellular expression levels of CCR5. The pDNA-CCL4 vaccination increased tumor growth and tumor rate in mice bearing D2F2/E2 tumors (Table 3) [121]. CCL4 has a good survival 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 (Table 4) [149, 151, 153, 155, 157, 176]. In cell models (Table 2), CCR5 expression had no effects on proliferation, but CC5 KD and antagonist reduced proliferation, colony formation, migration, invasion, and CCL5-inuced calcium flux, proliferation, glucose uptake, and intracellular ATP/pyruvate/G6P in parallel with decrease of CCL5-induced pAkt, pmTOR, and pGSK-3β, and arrest in the G1 phase [5, 6, 7, 33]. In animal models (Table 3), CCR5 antagonist reduced the number and the size of pulmonary metastases and bone metastasis but had no change in tumor growth in established tumors [5]. CCR5 is highly expressed in patients with BL and HER2 subtypes, compared to those with luminal subtypes (Table 4) [5]. A clinical trial (NCT03838367) is designed to investigate a phase Ib/II study of leronlimab (PRO 140) combined with carboplatin in patients with CCR5 positive metastaticTNBC (https://clinicaltrials.gov/search?cond=breast%20cancer&intr=ccr5). There is an open-label, non-randomized trial with OB-002 (CCR5 antagonist) monotherapy dose escalation in patients with metastatic breast cancer (NCT05940844, https://clinicaltrials.gov/search?cond=breast%20cancer&intr=ccr5).

3.6 Orphan Ligand CCL18

Although PITPNM3 is reported as a specific receptor for CCL18 [34], further studies require clarifying functional roles of chemokine receptor based on the similarity of CCR1-10. CCL18 induced migration in MDA-MB-231 cells (Table 2) [34] and intratumoral injection of CCL18 increased angiogenesis, lung/liver metastasis, vascular invasion, and lung weight (Table 3) [34, 122]. 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 (Table 4) [34, 151, 159, 168].

3.7 The CCL20-CCR6 Axis

CCL20 expression and treatment increased viability, migration, invasion, colony formation, chemoresistance, stemness and tumorsphere in parallel with increased uPA activity, MMP1, MMP2, MMP9, RANKL, OPG, ALDH, NANOG, OCT4, SOX2, pPKCζ, pp38, pp65, and ABCB1. On the other hand, CCL20 Ab and KD reduced viability, migration, invasion, colony formation, and chemoresistance in parallel with decreased ALDH in cell models (Table 2) [34, 35, 36, 37]. In animal models, CCL20 expression increased tumor growth, while CCL20 Ab reduced lung/bone metastasis (Table 3) [35, 36]. CCL20 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 (Table 4) [35, 36, 153, 157]. Studies on CCR6 in cell and animal models for breast cancer are lacking. CCR6 is related to pleura metastasis and aggressive stage but has no effects on overall survivals in patients with breast cancer (Table 4) [177, 178].

3.8 The CCL19/21-CCR7 Axis

CCL19 increased proliferation, migration, and invasion in parallel with increased N-cadherin, vimentin, pAkt and MMP2/9 and decreased E-cadherin (Table 2) [38]. Although CCL19 induced migration in PyVmT-CCR7 cells, it has no effects on proliferation (Table 2) [39]. Studies on CCL19 in animal models for breast cancer are lacking. CCL19 is related to aggressive status and shows increased risks in LA subtype, but a good prognosis and survival in patients with breast cancer. Interestingly, patients with ER positive cancers showed a good survival with plasma levels of CCL19 but a poor survival with tumoral levels of CCL19 (Table 4) [151, 155, 156, 157, 173, 178]. Although CCL21 had no effects on proliferation, it increased migration, invasion, and colony formation and decreased apoptosis in parallel with increased TAP-1, slug, vimentin, N-cadherin, pAkt, pErk, VEGF, and BclX and decreased TGF-β, FasL, E-cadherin, and Bmf. CCL21 induced migration in PyVmT-CCR7 cells but has no effects on proliferation (Table 2) [39, 40, 41, 42, 43, 44, 45, 46]. In animal models, treatment of CCL21 positive human lymphocytes reduced tumor growth and enhanced survival [42]. Mut-CCL21 treatment decreased lymph node metastasis but had no effects on tumor growth in mice bearing 4T1 cells (Table 3) [41]. CCL21 is highly expressed in metastatic breast cancers and has a good prognosis and survival (Table 4) [151, 155, 157, 160, 173, 179]. In cell models, CCR7 Ab and KD reduced both basal and CCL19-induced proliferation, migration, and invasion and increased apoptosis in parallel with decreased VEGF, CCL21-induced pAkt/pErk, EpCAM, and increased PVR (Table 2) [38, 45, 46, 47]. Compared to PyVmT-CCR7 negative cells, CCR7 positive cells increased tumor growth, lymph node metastasis, and lung metastasis [39], while CCR7 KD reduced tumor growth and node metastasis in animal models (Table 3) [47]. 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, between patients with breast cancer (Table 4) [43, 44, 47, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186].

3.9 The CCL1/16-CCR8 Axis

Studies on CCL1 in cell and animal models for breast cancer are lacking. CCL1 is highly expressed in invasive cancers and ER negative cancers and is related to tumor grade. CCL1 increased Treg infiltration and showed a poor survival in patients with breast cancer (Table 4) [168, 175]. CCL16 is described in section of the CCL3/5/7/8/14/15/16/23-CCR1 axis [156]. Studies on CCR8 in cell and animal models for breast cancer are lacking. A clinical trial (NCT06387628) is designed to evaluate the efficacy and safety of LM108 (CCR8 Ab) plus toripalimab plusnab-paclitaxel or eribulin as first-line or post-line treatment in patients with metastatic TNBC (https://clinicaltrials.gov/search?cond=breast%20cancer&intr=ccr8). There is a human study about the safety of BAY3375968 (CCR8 Ab) alone or in combination with pembrolizumab in patients with advanced solid tumors including BC (NCT05537740, https://clinicaltrials.gov/search?cond=breast%20cancer&intr=ccr8).

3.10 The CCL25-CCR9 Axis

In cell models, CCL25 increased proliferation, migration, and invasion and reduced cisplatin-induced apoptosis in parallel with increased MMP1/9/11/13. However, CCL25 had no effects on migration and invasion in MCF7 cells (Table 2) [48, 49]. Studies on CCL25 in animal models for breast cancer are lacking. CCL25 is highly expressed in TNBC and African Americans and shows a poor survival, particularly in African Americans (Table 4) [157]. CCR9 Ab reduced CCL25-induced proliferation, migration, and invasion in parallel with a decrease of CCL25-induced MMP1/9/11/13 (Table 2) [48, 49]. Studies on CCR9 in animal models for breast cancer are lacking. CCR9 is highly expressed in poorly differentiated breast cancers (Table 4) [49].

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. In cell models, CCL27 increased migration and invasion in parallel with increased pErk and MMP7 (Table 2) [50]. Chemotoxin CCL27-PE38 had no change in lung metastasis in mice bearing 4T1 cells (Table 3) [120]. In human breast cancer samples, CCL27 is highly expressed in inflammatory breast cancers (Table 4) [149]. CCR10 KD reduced CCL27-induced migration and invasion in parallel with decreased pErk and MMP7 in cell model (Table 2) [50]. Studies on CCR10 in animal models for breast cancer are lacking. CCR10 is related to capsular invasion, stage, and lymph node metastasis (Table 4) [50].

4. The CXCL-CXCR Axis
4.1 The CXCL6/7/8-CXCR1 Axis

Studies on CXCL6 in cell and animal models for breast cancer are lacking. In human breast cancer samples, CXCL6 is highly expressed in ER negative breast cancers and is related to metastasis of breast cancers, showing unchanging or good survivals (Table 4) [187, 188]. CXCL7 increased migration and invasion in parallel with increased pFak, MMP13, and VEGF. However, CXCL7 had no effects on migration in T47D and ZR-75-1 cells (Table 2) [4, 51, 52, 53]. In animal models, CXCL7 Ab reduced tumor growth and lung metastasis with decreased M2 Mφ infiltration (Table 3) [53]. In human breast cancer samples, CXCL7 is related to stage III of breast cancers and has controversial survivals: good, unchanging, and poor (Table 4) [53, 155, 187, 189, 190]. In cell models, CXCL8 increased mammosphere formation, migration, invasion, and chemoresistance but had no effects on proliferation in parallel with increased pHER2, pAkt, and pErk. On the other hand, CXCL8 Ab and KD reduced these effects including proliferation in parallel with decreased cyclin D1, pAkt, integrin β3, fibronectin, N-cadherin, vimentin, pSTAT3, and ALDH+ population, and increased p27. CXCL8 had no effects on migration in T47D cells (Table 2) [4, 54, 55, 56, 57, 58]. In animal models, CXCL8 induced angiogenesis (Table 3) [54]. 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 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 (Table 4) [149, 150, 153, 155, 159, 166, 176, 187, 188, 189, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200]. CXCR1 Ab and antagonist reduced cell viability and increased apoptosis in parallel with decreased ALDH, pAkt, and pFak and increased FASL (Table 2) [59]. In animal models, CXCR1 antagonist reduced tumor growth, the number of CSC cells, and metastasis in parallel with decreased ALDH, pAkt, and pFak. On the other hand, CXCR1 antagonist reduced tumor growth, but had no change in metastasis in mice bearing MDA-MB-453 cells (Table 3) [59]. In human breast cancer samples, CXCR1 is highly expressed in invasive breast cancers (Table 4) [174].

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

CXCL1 increased sphere formation, proliferation, migration, and invasion in parallel with increased vimentin, β-catenin, SOX4, pp65, pIκB, pErk, MMP2, and MMP and decreased E-cadherin. CXCL1 had no effects on migration and proliferation in T47D and PyMT cells, respectively. CXCL1 Ab and KD reduced the CXCL1-mediated effects in parallel with decreased fibronectin, N-cadherin, pSTAT3, and ALDH+ population (Table 2) [4, 58, 60, 61, 62, 63]. In animal models, treatment of THP1-M2/shCXCL1 cells reduced tumor growth and lung metastasis in parallel with decreased vimentin, SOX4, and pp65, and increased E-cadherin [60]. Chemokinostatin-1 also reduced tumor growth and angiogenesis [123]. In addition, TAM-shCXCL1 and shCXCL1/2 treatment decreased tumor growth and lung metastasis, showing reduced infiltration of CD11b(+)Gr1(+) myeloid cells (Table 3) [60, 124]. In human breast cancer samples, stromal CXCL1 is related to tumor grade and shows a poor prognosis. 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 (Table 4) [62, 153, 188, 201, 202, 203, 204]. CXCL2 KD reduced invasion in parallel with decreased fibronectin, N-cadherin, pSTAT3 and unchanged E-cadherin, vimentin, and ALDH+ population (Table 2) [58]. Studies on CXCL2 in animal models for breast cancer are lacking. In human breast cancer samples, CXCL2 is related to metastasis of breast cancer and shows a good prognosis and survival (Table 4) [187, 188, 190, 203]. CXCL3 induced cell migration and CXCL3 KD reduced invasion in parallel with decreased fibronectin, N-cadherin, pSTAT3 and unchanged E-cadherin, vimentin, and ALDH+ population. CXCL3 had unchanged migration in T47D and ZR-75-1 cells (Table 2) [4, 58]. Studies on CXCL3 in animal models for breast cancer are lacking. In human breast cancer samples, 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 (Table 4) [187, 188, 189, 190, 203, 205]. CXCL5 had no effect on proliferation in PyMT cells and CXCL5 Ab reduced MSC-CM induced migration (Table 2) [63]. Studies on CXCL5 in animal models for breast cancer are lacking. CXCL6, CXCL7, and CXCL8 are described in section of the CXCL6/7/8-CXCR1 axis. In human breast cancer samples, CXCL5 is highly expressed in breast cancers and ER negative cancers and is related to low metastasis in LB subtype. CXCL5 has no effects on survival (Table 4) [153, 161, 168, 176, 188]. CXCR2 had no effects on proliferation but increased colony formation, migration, and invasion in parallel with increased pAkt, β-catenin, Bid, Bcl2, and Bcl-xL and decreased E-cadherin, PI3K-P85α, Bax, Bak, and Bad [64]. CXCR2 Ab, inhibitor, and KD also did not affect cell proliferation but reduced the CXCR2-mediated effects [51, 56, 63, 64, 65, 66]. Furthermore, CXCR2 KD enhanced paclitaxel/doxorubicin-induced apoptosis and sensitivity (Table 2) [65, 66]. In animal models, CXCR2 KD reduced tumor growth, metastasis, and taxol resistance in mice bearing MDA-MB-231 cells [64]. On the other hand, mice bearing CXCR2 KD Cl66 cells showed no effect on tumor growth with controversial metastasis and further decreased paclitaxel-reduced tumor growth, metastasis, and angiogenesis in parallel with increased caspase-3 and unchanging PCNA (Table 3) [65, 66]. The different response to tumor growth may be related to the different immune response between intact and T/B cell deficient mice. Interestingly, CXCR2 KO mice had increased tumor growth and metastasis in parallel with increased TAN and decreased TAM infiltration, showing reduced killing ability of CXCR2 KO TANs (Table 3) [125]. In human breast cancer samples, 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 shows good or poor survivals in patients with breast cancers. Interestingly, CXCR2 C1208T variation increased the risk of breast cancer, leading to a poor survival (Table 4) [64, 174, 200, 206, 207, 208].

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

CXCL4 reduced CXCL12-induced migration and CXCL447-70 decreased cell proliferation (Table 2) [67, 68]. In animal models, CXCL447-70 decreased tumor growth in parallel with increased tumoral mRNA levels of F4/80, CD11c, and IFN-γ (Table 3) [68]. Studies on CXCL4 in human breast cancer samples are lacking. CXCL9 induced cell migration by increasing MMP9 (Table 2) [69, 70]. Interestingly, CXCL9 Ab increased tumor growth in mice bearing 4T1 cells (Table 3) [126]. In human breast cancer samples, CXCL9 is highly expressed, 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 (Table 4) [153, 155, 159, 160, 187, 189, 190, 203, 209]. CXCL10 induced cell migration in parallel with increased ALDH1+ cells, pSTAT3, pErk, pCREB, pRhoA, pCdc42, MMP9, p65, and NF-κB activity. However, CXCL10 did not affect cell migration in T47D and ZR-75-1 cells (Table 2) [4, 69, 70, 71, 72]. Studies on CXCL10 in animal models for breast cancer are lacking. In human breast cancer samples, 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 survivals (Table 4) [153, 159, 187, 190, 203, 210, 211, 212]. CXCL11 had no effect on proliferation but induced cell migration by increasing ALDH1+ cells, pSTAT3, pErk, pCREB, and MMP9 (Table 2) [69, 70, 71, 73]. Studies on CXCL10 in animal models for breast cancer samples are lacking. In human breast cancer samples, 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 (Table 4) [153, 159, 203]. CXCR3B expression increased CSC population and tumorsphere in parallel with increased ALDH1+ and CD44+CD24- cells, while CXCR3B KD reduced these effects. CXCR3 antagonist and KD reduced cell migration with unchanged proliferation by decreasing p65 and NF-κB activity (Table 2) [69, 70, 71, 72, 74]. In animal models, CXCR3 antagonist and KD did not affect tumor growth but reduced migration by increasing splenic CD3, CD4, and CD8 cells (Table 3) [69, 71, 74]. In human breast cancer samples, 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 (Table 4) [74, 213, 214, 215].

4.4 The CXCL12-CXCR4 Axis

CXCL12 increased proliferation, migration, invasion, colony formation, S and G2/M phases, and adhesion and decreased apoptosis and calcium flux in parallel with increased RhoA, Rac1, BclX, pHER2, pEGFR, pSTAT3, pErk, and pAkt and decreased Bmf. Some reports showed that CXCL12 decreased proliferation, unchanged invasion, and apoptosis in MDA-MB-231 cells, and had no effects on migration in T47D, BT474/BT547, and SUM-149 cells. Although CXCL12 Ab and KD had no change in proliferation, it reduced transendothelial migration (Table 2) [40, 43, 46, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88]. In animal models, CXCL12 increased tumor growth and ICI-inhibited tumor growth, preferring human HER2 cancers to TNBC or LA subtype [127]. CXCL12 expression increased tumor growth in orthotropic model and reduced lung metastasis in pulmonary metastasis model with increased survivals in mice bearing MDA-MB-231 cells, while CXCL12 Ab decreased lymphatic vessel and lymph node metastasis [81, 128]. Compared to CXCL12 mutant, CXCL2 WT reduced tumor growth and lung metastasis in mice bearing 4T1 cells, showing increased DC in lymph nodes and decreased splenic MDSC. Treatment of CXCL12-EV stromal cells decreased lung metastasis in mice bearing 4T1 cells [129, 130]. CXCL12 Ab had no effects on tumor growth in mice bearing MCF-7 cells but reduced these effects in CXCL12 positive CAF-induced tumors [83, 131]. Fibroblast CXCL12 cKO mice showed decreased tumor growth, lung metastasis, and angiogenesis after MVT1 cell orthotropic injection, leading to an increased survival [87]. These results indicate the involvement of CXCL12+ fibroblasts in breast cancer progression. In addition, CXCL12 expression had no change in tumor growth but increased invasion and angiogenesis with augmented TAM infiltration in mice bearing MTLn3 cells (Table 3) [132]. In human breast cancer samples, CXCL12 is highly expressed in breast cancers and BL subtype 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, particularly who have high plasma levels of CXCL12 and CXCL12δ isoform. Some studies show no change in CXCL12 levels between subtypes and survivals (Table 4) [82, 155, 160, 168, 187, 189, 190, 203, 216, 217, 218, 219, 220, 221, 222]. CXCR4 increased cell invasion in parallel with increased cadherin11, ZEB-1, MMP-2, pErbB2, pEGFR, pMet, pIGFRβ, MDM2, p53, c-Myc, survivin, and cyclin D1 and decreased p27. Interestingly, CXCR4 decreased E-cadherin in MCF-7 cells but increased it in MCF10A cells. CXCR4 Ab, antagonist, and KD reduced proliferation, basal and hypoxia-/CXCL12-induced migration and invasion, and transendothelial migration and increased apoptosis in parallel with decreased pSTAT3, pAkt, GSK-3, pJak2, and cMyc. However, some reports showed no change of proliferation in MCF-7 and 4T1 cells (Table 2) [46, 75, 77, 78, 80, 83, 89, 90, 91, 92, 93, 94, 95, 96, 97]. In animal models, CXCR4 increased tumor growth, metastasis, invasion, and lymphatic invasion with decreased E-cadherin [91, 131, 133]. CXCR4 Ab, inhibitors, and KD reduced tumor growth, metastasis, and angiogenesis in parallel with decreased pAkt, pErk, pFak, and Bcl-2 and increased Bax and caspase-3, showing reducing TAM and Treg infiltration, but had no change in survivals (Table 3) [43, 77, 78, 85, 89, 90, 96, 97, 134, 135, 136, 137, 138]. Although CXCR4 inhibitors reduced tumor growth, metastasis, and angiogenesis in mice bearing human HER2+ cells, it had no change in these effects in mice bearing human TNBC cells [127]. CXCR4 Ab, inhibitor, and KD had no effect on tumor growth in mice bearing MCF-7 cells but reduced tumor growth with cotreatment of CAF. Interestingly, CXCR4 inhibitor decreased ABCG2 in mice bearing tamoxifen-resistant MCF-7 cells, leading to reduced tumor growth [83, 93]. In addition, vaccinia viruses for CXCR4 reduced tumor growth and metastasis in parallel with decreased CD31, Ki67, VEGF, and bone marrow-derived endothelial and myeloid cells, resulting in increased survival (Table 3) [139]. In human breast cancer samples, 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 (Table 4) [43, 94, 131, 174, 177, 181, 182, 185, 213, 214, 216, 217, 218, 219, 221, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243]. A clinical trial (NCT05103917) is designed to evaluate the safety and tolerability of X4P-001 (CXCR4 inhibitor) combined with toriplimab in patients with locally advanced or metastatic TNBC (https://clinicaltrials.gov/search?cond=breast%20cancer&intr=CXCR4).

4.5 The CXCL13-CXCR5 Axis

CXCL13 in combination with CXCR5 expression increased migration in parallel with augmented vimentin, slug, snail, N-cadherin, RANKL, MMP9, and pSrc, particularly decreasing E-cadherin in T47D cells [98]. CXCL13 Ab reduced proliferation and increased apoptosis in parallel with decreased pErk and cyclin D1 and increased caspase-9 (Table 2) [99]. Studies on CXCL13 in animal models for breast cancer are lacking. In human breast cancer samples, CXCL13 is highly expressed in breast cancers, ER negative cancers, and metastatic breast cancers and is related to lymph node metastasis with CXCR5 coexpression and increased Ki67. CXCL12 has a good prognosis and both unchanged and good survivals in patients with breast cancers (Table 4) [52, 98, 155, 160, 168, 187, 189, 190, 203, 209]. CXCR5 Ab reduced migration in parallel with decreased vimentin, slug, snail, N-cadherin, and RANKL and increased E-cadherin in CXCL13-treated CXCR5 expression cells (Table 2) [98]. Studies on CXCR5 in animal models for breast cancer are lacking. In human breast cancer samples, CXCR5 is related to lymph node metastasis and tumor stage (Table 4) [199].

4.6 Orphan Ligand CXCL14

CXCL14 expression reduced proliferation and invasion in MDA-MB-231 cells (Table 2) [100]. In animal models, CXCL14 expression reduced tumor growth, lung metastasis, and angiogenesis, showing decreased myeloid cells and Treg and increased CD8 infiltration in primary tumors and decreased TAM and Treg and increased CD8 infiltration in lung metastatic tumors (Table 3) [100, 140]. In human breast cancer samples, CXCL14 is related to lymph node metastasis and has good survivals in all breast cancers and BL/HER2/LA subtypes (Table 4) [100, 140, 155, 187, 189].

4.7 The CXCL16-CXCR6 Axis

CXCL16 promoted migration, invasion, and F-actin polymerization in MDA-MB-231 and MCF-7 cells (Table 2) [101]. Studies on CXCL16 in animal models for breast cancer are lacking. In human breast cancer samples, CXCL16 increased the risk of cancer in HER2 subtype [156] and was related to stage (Table 4) [101]. CXCR6 Ab reduced CXCL16-induced migration, invasion, and F-actin polymerization in cell models (Table 2) [101]. CXCR6 KO mice showed no change in tumor growth but increased radiation-reduced tumor growth (Table 3) [141]. CXCR6 in human breast cancer samples is related to stage (Table 4) [101].

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. In cell models, CXCR7 expression increased cell proliferation, while CXCR7 inhibitor and KD reduced proliferation and CXCL12-induced migration in parallel with decreased cyclin B1, Cdk4, pErk, EGF-induced pErk, pEGFR, pSTAT3, VCAM-1, MMP2, MMP9, and S-phase, and increased p21 and G0/G1 phase in cell cycle (Table 2) [73, 88]. In animal models, CXCR7 expression increased tumor growth but had no effect on invasion although it induced reduction in both metastasis and VEGF levels. On the other hand, CXCR7 inhibitor and KD caused no change in tumor growth or reduce tumor growth and metastasis in parallel with decreased pSTAT3, pErk, CD31, Ki67, cyclin D1, and MMP9 by downregulating TAM infiltration (Table 3) [88, 130, 142]. Interestingly, endothelial CXCR7 cKO treatment in lung metastasis model increased tumor growth and metastasis and showed no change in angiogenesis, leading to a poor survival (Table 3) [143]. In human breast cancer samples, CXCR7 is highly expressed in TNBC, ER/PR negative or positive cancers and is related to TNM stage and tumor grade, showing a poor survival (Table 4) [88, 218, 244].

4.9 The CXCL17-CXCR8 (GPR35) Axis

In cell models, CXCL17 KD reduced proliferation and migration and CXCL17 increased pErk (Table 2) [102]. CXCL17 expression increased tumor growth in animal model (Table 3) [102]. In human breast cancer samples, CXCL17 is highly expressed in ER negative cancers and is related to Ki67 expression with a poor survival (Table 4) [102, 153]. CXCR8 KD decreased CXCL17-induced pErk in MCF7 cells (Table 2) [102]. Studies on CXCR8 in animal models for breast cancer are lacking. CXCR8 is related to tumor grade and Ki67 expression, showing no change in overall survival (Table 4) [102].

5. The CX3CL-CX3CR Axis
The CX3CL1-CX3CR1 Axis

CX3CL1 increased proliferation in T47D cells by increasing pErk, pErbB1, and pErbB2 levels (Table 2) [98]. In animal models, intratumoral injections of Ad-CX3CL1 increased palpable tumors but had no change in angiogenesis. CX3CL1 KO showed unchanged or delayed mammary tumor onset, unchanged or decreased tumor number without alteration in tumor growth (Table 3) [103]. In human breast cancer samples, 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 (Table 4) [149, 153, 245, 246]. CX3CR1 expression increased pErk in MDA-MB-436 cells (Table 2) [103]. CX3CR1 expression increased bone metastasis in intracardiac injection models, while CX3CR1 KO mice showed reduced bone metastasis (Table 3) [103]. In human breast cancer samples, CX3CR1 is related to brain metastasis but has no change in survival (Table 4) [177].

6. Summary

In breast cancer cell models, chemokine axes play a key role in cell migration and invasion, showing positive effects on cell viability, angiogenesis, cell cycle, stemness, and chemoresistance but negative effects on autophagy, apoptosis, and necrosis (Fig. 1). Because some breast cancer cells are less responsive to chemokines, significant roles of chemokine axes in breast cancer cells are likely to be quite dependent on signature of chemokines and chemokine receptors which breast cancer cells express. In addition, chemokine axes may be involved in cellular metabolism by increasing calcium flux, glucose uptake, glycolysis, intracellular ATP/pyruvate/G6P, and GLUT-1 (Fig. 1) which require cancer cell growth and spread. In animal models for breast cancer cells, chemokine axes play a crucial role in tumor growth, metastasis, and angiogenesis, as well as immune contexture in the tumor microenvironment by increasing TAM and MDSCs, which affect overall survivals (Fig. 1). Differently from single cell models, animal models may appear to have various chemokine axes between tumor cells, stromal cells, immune cells, and adipocytes in the breast tumor microenvironment, showing complex interaction which makes hard to simply explain with single chemokine axis. In human breast cancer, chemokine axes appear to play a critical role in immune contexture by recruiting immune cells, such as TAM, Treg, CD20, and CD133 cell, probably affecting prognosis and overall survivals (Fig. 1). Some chemokine axes are related to clinical features, such as tumor grade, stage, size, lymph node metastasis, and breast cancer subtypes, showing increased Ki67 in tumor tissues. Based on the integrated results from cell and animal models and clinical aspects, the CCL2-CCR2 axis, the CCL3/5-CCR5 axis, the orphan chemokine CCL18, the CXCL1/8-CXCR2 axis, and the CXCL12-CXCR4/7 axis play a significant role in chemokine-induced breast cancer progression. Interestingly, orphan chemokine CXCL14 looks like to block the harmful roles of some chemokine axes in breast cancer (Fig. 1), supporting benefits for breast cancer. In conclusion, chemokine axes are involved in breast cancer progression via tumor growth, migration, invasion, and angiogenesis in the tumor microenvironment, as well as systemic metastasis. Furthermore, inhibitors and antibodies to disrupt specific chemokine axes have diminished chemokine-derived breast cancer progression, providing the adjuvant therapeutic options to enhance the effectiveness of conventional therapeutic strategies.

Fig. 1.

Functional roles of chemokine axis in cell and animal models and human breast cancers. The chemokine-induced signaling pathways are inside circles for each model, biological effects of chemokines are on the circular lines (color blocks), and the contributed chemokine axis and chemokines are outside circles of each model (square boxes). Red: positive effects; blue: negative effects. In box, bold: chemokine axis; roman: chemokine or chemokine receptor. In survival box, red: poor survival; blue: good survival; gray: controversial; black: no effects.

Author Contributions

D-SS and SEA designed the research review. D-SS wrote original draft preparation. Both authors contributed to editorial changes in the manuscript. Both authors read and approved the final manuscript. Both authors have participated sufficiently in the work to take public responsibility for appropriate portions of the content and agreed to be accountable for all aspects of the work in ensuring that questions related to its accuracy or integrity.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

Not applicable.

Funding

This research was funded, in whole or in part, by National Institutes of Health (NIH) as the following grants: NCI SC1CA200519 (D.-S.S.), NCI P50CA098131 (D.-S.S.), U54MD007586 (S.E.A.), U54CA163069 (D.-S.S., S.E.A.), and ACS DICRIDG-21-071-01-DICRIDG (D.-S.S., S.E.A.).

Conflict of Interest

The authors declare no conflict of interest.

References

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