Estrogen-regulation of CXCL12 axis and involvement in breast cancer cell proliferation

Abstract

PosterBreast cancer accounts for one-third of cancer diagnoses and is a primary cause of cancer death among women in Western countries. About 70% of breast cancers express estrogen receptor alpha (ERα). Considerable data showed a mitogenic action of estrogen (E2) through ERα in these hormone-dependent cancers. Notably, the regulation of cytokine CXCL12 seems to be a key mediator of the growth effect of E2 in breast cancer. This cytokine is also known to play an important role in cell survival and migration during embryonic development and in adult. Two G protein-coupled receptors, CXCR4 and CXCR7, are known to bind CXCL12. The first one, CXCR4, has been widely studied in cell migration and in metastatic potential of tumor cells that over-express this chemokine receptor. In contrast, involvement of the second receptor, CXCR7, which was discovered more recently as a target of CXCL12, remains unclear in carcinogenesis. The aim of our study was to examine the regulation of the CXCL12 axis components by E2 and selective ER modulators including agonists and antagonists. For this purpose, we have analysed E2-regulation of CXCL12, CXCR4 and CXCR7 mRNA and protein levels by quantitative real-time PCR, Western-blot, ELISA or FACS analysis in ER-positive MCF-7 breast cancer cells. Interestingly, our data showed, for the first time, that CXCR4 and CXCR7 chemokine receptors are differentially regulated by E2, in a dose- and time-dependent manner. While the expression of CXCL12 and CXCR4 transcripts and proteins are positively regulated by E2 and xeno-estrogens, the expression of CXCR7 is negatively regulated. Surprisingly, at low concentrations, anti-estrogens increased the expression of CXCR4 transcript but not those of CXCL12 and CXCR7. Furthermore, the importance of CXCL12 axis was evaluated on basal and E2-dependent MCF-7 cell proliferation by using specific siRNA directed against CXCL12, CXCR4 and CXCR7. This analysis demonstrated that the E2-regulation of CXCL12 axis contributes to the effect of E2 in breast cancer cell proliferation