Abstract 3916: Inhibition of GREB1 mRNA and protein limits ER+ breast tumor cell proliferation

Abstract

Discovering the mechanism by which estrogen regulates breast cancer growth will aid in the identification of patients who will benefit from endocrine therapy. Estrogen (E2) binding to the estrogen receptor (ER) stimulates the proliferation of normal mammary cells and some breast cancers. Preventing ER expression or receptor-ligand interaction in hormone-responsive breast cancers inhibits cell division and promotes tumor cell death. However, the mechanism of E2-regulated breast cancer cell growth remains unclear. Although E2-regulated genes have been identified, those critically involved in growth regulation remain elusive. Identification of critical E2-regulated genes involved in mammary cell proliferation would elucidate the key pathway(s) supporting hormone-mediated tumor growth as well as provide insight into mechanisms of resistance to endocrine therapies and potential prognostic and therapeutic targets for ER+ breast cancer treatment. Gene regulated in breast cancer 1 (GREB1) is an estrogen-regulated gene that has been implicated in hormone-stimulated cell proliferation and is a candidate clinical marker for response to endocrine therapy. GREB1 mRNA and protein expression correlate with ER expression in breast tumors and the addition of estrogen to ER+ breast cancer cell lines leads to an increase in GREB1 expression and cell proliferation. The function of GREB1 and its role in ER+ breast tumors remains undefined. Experiments were designed to elucidate the role of GREB1 in ER+ breast cancer cell lines. ER+ breast cancer cell lines were transfected with GREB1-specific siRNA and control species. These tumor cell populations were evaluated for GREB1 mRNA and protein expression, cell growth and proliferation as well as invasion and migration in vitro. Sequence-specific siRNA effectively inhibited GREB1 mRNA and protein expression for more than 96 hours in MCF7 and T47D ER+ breast tumor cell lines. Utilizing the real-time Xcelligence system to monitor cell growth in culture suggested tumor cells treated with siRNA targeting GREB1 had significantly retarded cell proliferation. These observations suggest that GREB1 is a critical E2-regulated gene involved in breast tumor cell proliferation and is an exploitable target for novel breast cancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3916. doi:1538-7445.AM2012-3916