Down-regulation of CXCL12 by hypermethylation induces cell proliferation, growth and invasion in triple-negative breast cancer

We previously reported that CXCL12 was reduced in breast cancer, and its expression was associated with clinicopathological factors and prognosis. However, the epigenetic regulation and molecular functions of CXCL12 in Triple-negative breast cancer (TNBC) remain unknown. In this study, CXCL12 expression levels and methylation status of its promoter region in TNBC cell lines and TNBC tissues (n=105) as well as normal breast tissues (n=105) were assessed by RTq-PCR and methylation analysis, respectively. The cellular functions of CXCL12 on TNBC cell proliferation, growth and invasion were investigated in vivo and in vitro. Our data revealed that CXCL12 was frequently silenced by promoter hypermethylation in both tested TNBC cell lines and primary TNBC, and correlation analysis between methylation status and clinicopathological parameters found that TNBC methylation was significantly correlated with lymph node status and TNM stage, while no significant correlation was found in other parameters. In addition, demethylation treatment resulted in re-expression of CXCL12 in TNBC cell lines, and cellular function experiments revealed that restoration of CXCL12 inhibited MDA-MB-231 cell proliferation and suppressed cell invasion. Furthermore, animal studies revealed that nude mice injected with the Lentivirus-CXCL12 cell lines featured a lighter weight than the control cells. These data suggest that CXCL12 may function as a tumor suppressor gene, which is down-regulated through promoter hypermethylation in TNBC development.