Abstract 1469: Cyclin D1 plays a critical role in the response of mammary gland to estrogen and progesterone by regulating progesterone receptor expression

Abstract

Abstract Estrogen and progesterone are important hormones in normal female development, yet both have critical roles in breast carcinogenesis. Cyclin D1 is a breast cancer oncogene whose amplification is linked to poor prognosis in estrogen and progesterone receptor positive breast cancers. Here we show that cyclin D1 regulates progesterone receptor expression, consequently enhancing responses to estrogen and progesterone in breast development and carcinogenesis. Estrogen treatment of cyclin D1 transgenic mice caused mammary hyperplasias expressing increased progesterone receptors, which were stimulated by progesterone and blocked by a progesterone antagonist. Cyclin D1 regulated progesterone receptor expresion through a novel estrogen- and cyclin D1-responsive enhancer in DNA encoding part of the 3’ untranslated region of the progesterone receptor gene. Small inhibitory RNAs for cyclin D1 decreased progesterone receptor expression in human breast cancer cells, which sensitized them to progesterone-antagonists. Since estrogen and progesterone regulate cyclin D1, our results suggest that cyclin D1's participation in a feed-forward loop could contribute to increased breast cancer risks associated with estrogen and progesterone combinations. Additionally, its regulation of the progesterone receptor identifies a novel role for cyclin D1 in ovarian hormone control of breast development and breast carcinogenesis. 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 1469.