Cyclin D1 Enhances the Response to Estrogen and Progesterone by Regulating Progesterone Receptor Expression

Abstract

Estrogen and progesterone are the defining hormones of normal female development, and both play 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 report that cyclin D1 regulates progesterone receptor expression, consequently enhancing responses to estrogen and progesterone. Estrogen treatment of cyclin D1 transgenic mice increased progesterone receptor expression and induced mammary hyperplasias that were stimulated by progesterone and blocked by a progesterone antagonist. Progesterone receptor levels decreased in cyclin D1 knockout mice. Cyclin D1 regulated progesterone receptor expression 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 and estrogen receptor binding to the 3′ enhancer region in human breast cancer cells. 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.

For this work, C. Yang, L. Chen, and E. V. Schmidt were supported by a grant from the National Cancer Institute of the National Institutes of Health (grant RO1 CA69069). C. Yang received additional support from grant R01 CA112021, and both E. V. Schmidt and L. Chen received support from grant U01 AI07033. C. Li was supported by the Harvard Breast Cancer SPORE grant P50 CA89393.

We gratefully acknowledge review of the histology results determined for our mice by Robert Cardiff of the University of California at Davis.