Abstract LB-93: The epigenetic basis of the tumorigenic action of retinoic acid

Abstract

Abstract Preformed vitamin A, or Retinol, is found in animal foods, such as liver and whole milk, and in some fortified food products. Carotenoids, such as beta-carotene from fruit and vegetables, are also efficiently converted into Retinol. Retinol, once converted into its bioactive form, retinoic acid (RA), plays a major role in cell division, cell death, and cell differentiation. We found that RA can exert a double-edged action: it can either inhibit, or promote, tumorigenesis according to the functional status of one of its receptors, the RA receptor alpha (RARA). Further, we found that RA, through RARA, controls a network of tumor suppressor genes governing cell death, cell proliferation, cell differentiation, migration, and invasion. Finally, we observed that concomitant with epigenetic silencing of the tumor suppressor gene network, due to loss/functional inhibition of RARA, RA exerts a clear tumor-promoting action, raising the question as to whether dietary sources of RA, or RA precursors, can also promote tumorigenesis in cells with an impaired RARA. Using an isogenic breast cancer cell model (T47D), comprising two clonal cell lines, one with a functional RARA-regulated gene network (T47DLXC5) and one without functional RARA (T47DDNC8) (Ren et al., MCB, 2006), we generated subcutaneous xenograft tumors in athymic female nude mice. A 6-week diet with either RA (5 or 10 mg/kg) or Retinol (50 mg/kg) induced an opposite effect on xenograft tumor growth. T47DDNC8 xenograft tumors were stimulated to grow and metastasize to distant sites by RA/Retinol, while T47DLXC5 xenograft tumors were growth-inhibited by RA/Retinol, and did not invade. In breast cancer RARA function is often impaired due to a variety of upstream causes, including faulty RA transport by CRABP2 onto RARA and/or loss of Estrogen Receptor alpha (ERA), a pivotal RARA transcriptional regulator. Early detection of epigenetic silencing of tumor suppressor genes of the RARA network can be used to prevent tumorigenic effects of dietary sources of RA on breast tumorigenesis. This work was funded by R01 CA127614 (NS), PRIN 2007 (LT, SR). 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 LB-93.