Abstract
The chemokine (C-C motif) ligand 2 (CCL2) with its cognate receptor chemokine (C-C motif) receptor 2 (CCR2) plays important roles in tumor invasion and metastasis. However, the mechanisms and mediators for autocrine CCL2 and CCL2-CCR2 axis remain elusive in breast cancer. Here we examined the levels of CCL2 in 4 breast cancer cell lines along with 57 human breast cancer specimens and found them significantly increased with presence of 17β-estradiol (E2) in estrogen receptor (ER)-positive breast cancer cells, while anti-estrogen treatment weakened this enhancement. CCL2 expression positively correlated with Twist staining and aggressiveness of breast cancer. Estrogen exposure facilitated the proliferation, invasion and metastasis of hormone-dependent breast cancer and promoted angiogenesis via the increased secretion of CCL2 in vitro and in vivo, which could be suppressed by disruption of CCL2-CCR2 axis with CCR2 antagonist RS102895. Knockdown of Twist in MCF-7 cells significantly inhibited E2-induced CCL2 production, indicating an essential role of Twist in CCL2 regulation under estrogenic condition. Our data show the hormonal regulation on CCL2-CCR2 axis is associated with enhanced Twist expression via activation of ERα and PI3K/AKT/NF-κB signaling. Thus, CCL2-CCR2 axis may represent as a novel therapeutic target eagerly needed for hormone-dependent breast cancer.
Highlights
Chemokines are a family of cytokines with small molecular mass and chemotactic ability
IHC staining results showed positive signals of CCL2 were primarily located in the cytoplasm of tumor cells (Fig. 1d). 36 (63.2%) out of the 57 cases were positive for CCL2
Our findings indicate the critical roles of CCL2-CCR2 axis in the proliferative and metastatic properties of breast cancer cells, which is consistent with several previous studies[10,11]
Summary
Chemokines are a family of cytokines with small molecular mass and chemotactic ability. CCL2 has been shown to play crucial roles in breast and prostate tumor progression by facilitating cancer cell proliferation and survival, recruiting macrophages, and inducing angiogenesis through multiple mechanisms, including increasing survivin expression by activation of PI3K/ AKT pathway and direct induction of vascular endothelial growth factor-A (VEGF-A) through activation of p42/44 mitogen-activated protein kinase (MAPK)[12,13,14,15]. A total blockade of CCL2 both from the tumor and the stroma decreased recruitment of CCR2+ monocytes, inhibited tumor metastasis and extended survival time of tumor-bearing mice[10,16] Despite of those experimental studies that strongly support CCL2 as a pro-tumorigenic role in breast cancer, therapeutics aimed at interfering CCL2-CCR2 axis have turned out to be disappointing in www.nature.com/scientificreports/. CCL2-CCR2 axis is a novel therapeutic target for hormone-dependent breast cancer
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