Abstract 1716: BRCA1 expression modulates apoptosis and survival in response to retinoic acid in breast cancer cells

Abstract The vitamin A metabolite retinoic acid (RA) plays key roles in development, cell proliferation and differentiation. RA derivatives also display anti-cancinogenic activities. The different physiological effects of RA are mediated by retinoic acid receptors (RARs) and retinoid-X receptos (RXRs) that are transcription factors and members of the nuclear hormone receptor superfamily. Transcriptional activation by RA trigger cell cycle arrest, differentiation and apoptosis in certain tissues and cell types but in other tissues RA appear to promote rather than inhibit cell survival. Recently, RA derivatives were shown to bind and activate the orphan nuclear hormone receptor, peroxisome proliferator-activated β/δ (PPARβ/δ) when it hetrodimerizes with RXR. The partitioning of RA between the RAR and PPARβ/δ receptors is regulated by the balance between two intracellular lipid binding proteins: cellular retinoic acid binding protein II (CRABPII) and fatty acid binding protein 5 (FABP5). While CRABP-II delivers RA to RAR-RXR and facilitates anti-proliferative effects, FABP5 shuttles RA to PPARβ/δ-RXR and promotes pro-survival functions. Interestingly, the breast and ovarian tumor suppressor, BRCA1 and RA share the ability to direct cell-cycle arrest and apoptosis, and both BRCA1 and RA regulate transcription and chromatin structure. We hypothesize that BRCA1 and RA pathways work in concert to inhibit cell growth in breast cancer cells. We found that the inhibitory effects of all-trans RA (ATRA) and 9-cisRA correlate with BRCA1 expression. Both RA derivatives inhibited BRCA1-proficient MCF7 breast cancer cells growth by inducing apoptosis. ATRA and 9-cisRA did not inhibit the growth of BRCA1-null or BRCA1-silenced breast cancer cells despite similar levels of RA receptors (RAR and RXR) expression. We show here that in BRCA1-proficient cells, the FABP5/CRABP-II ratio is constant facilitating apoptotic cell death, while in BRCA1-deficient cells FABP5/CRABP-II ratio is elevated, and coincides with increased phosphorylation of the pro-survival factor, AKT, supporting RA-mediated cell survival. Additional apoptotic and cell cycle genes were differentially regulated between BRCA1-deficient and proficient cells in response to RA. However, RA-induction of the metabolic enzyme CYP26 gene expression was not altered between BRCA1-deficient and proficient cells, suggesting the cooperation between RA and BRCA1 is affecting cell proliferation but not necessarily all spectrum of RA signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1716.