GREB1 is a critical regulator of hormone dependent breast cancer growth

Abstract

Summary Background Estrogen plays a central role in breast cancer pathogenesis and many potent risk factors for the development of the disease can be explained in terms of increased lifetime exposure to estrogen. Although estrogen regulated genes have been identified, those critically involved in growth regulation remain elusive. Methods. To identify candidate genes involved in estrogen stimulated breast cancer growth, DNA microarray based gene expression profiles were generated from three estrogen receptor α (ERα) positive breast cancer cell lines grown under multiple stimulatory and inhibitory conditions. Results Only three genes were significantly induced by 17β-estradiol (E2) relative to control in all three cell lines: GREB1, stromal cell-derived factor 1 (SDF-1) and trefoil factor 1 (pS2). Quantitative real-time PCR assays confirmed that in all three cell lines, GREB1 was induced by E2, but not by the antiestrogens tamoxifen (TAM) or ICI 182,780. GREB1 expression level was strongly correlated with ERα positivity in 39 breast cancer cell lines of known ERα expression status. GREB1 induction by E2 was rapid (7.3 fold by 2 h for MCF-7) and mirrored the fraction of cells entering S-phase when released from an estrogen deprivation induced cell arrest. Suppression of GREB1 using siRNA blocked estrogen induced growth in MCF-7 cells and caused a paradoxical E2 induced growth inhibition. Conclusion These data suggest that GREB1 is critically involved in the estrogen induced growth of breast cancer cells and has the potential of being a clinical marker for response to endocrine therapy as well as a potential therapeutic target.