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.We have long known that ovarian hormones control normal breast development (13). Likewise, the connection between ovarian hormones and breast cancer was first therapeutically exploited over 100 years ago (3). While estrogen and progesterone (Pgr) combine to regulate normal breast development during pregnancy, the Women's Health Initiative study of hormone replacement has clearly demonstrated an increased breast cancer risk when progestins are combined with estrogen (7). This result reinvigorated the view that combinations of progesterone with estrogen can be carcinogenic.Cyclin D1 (CCND1) is a multifunctional G 1 -phase cyclin whose regulatory effects are particularly important in breast development and cancer (44). The cloning of cyclin D1 at 11q13 translocation breakpoints in parathyroid and mantle cell tumors was strong evidence of its oncogenic function, and evidence indicating that D1 was a G 1 cyclin was a key finding that linked cancer to perturbations of the cell cycle. Extensive evidence links cyclin D1 to cyclin-dependent kinase regulation of the cell cycle (27), although a recent report demonstrates that it also acts in transcriptional control (4). 11q13 amplification has been repeatedly demonstrated in breast cancers (22) where CCND1 overexpression has been linked to estrogen and progesterone receptor (PR) status. This linkage was first attributed to cyclin D1's regulation by estrogen and progesterone (12, 37). In this model, CCND1 is proposed to contribute to poor treatment response of estrogen receptor (ER)-positive tumors by acting downstream to promote hormone agonist...

miRNAs and estrogen action

“…There is some evidence that cyclin D1 acts as an ERα coactivator by direct interaction with the receptor C-terminal activation domain AF-2 [62], although ChIP studies fail to confirm direct recruitment of cyclin D1 and ERα to regulate PGR expression [63]. Infection of MCF-7 cells with a retroviral vector for the miR-17/20 cluster (including miR-17-5p, 18a, 19a, 20a, 19b, and 92) suppressed cyclin D1 expression and cell proliferation [64].…”

Progesterone receptors, their isoforms and progesterone regulated transcription

“…Cyclin D1 enhances PR levels via an enhancer that binds both ER and Cyclin D1 in the 3′-UTR of the PR gene (Yang et al , 2010). However, a single pulse of liganded PR suppresses cyclin levels including those of Cyclin D1 (Groshong et al , 1997) apparently through PR and AP1 regulatory elements in the distal Cyclin D1 promoter (Cicatiello et al , 2004).…”

Comparison of Increased Aromatase versus ERα in the Generation of Mammary Hyperplasia and Cancer

“…PR-B plays a role in alveologenesis, while PR-A is involved in ductal development and side branching (16). Cyclin D1 and c-Myc are both ERα and PR downstream genes, while amphiregulin, nuclear factor kappa B ligand (RANKL), and Wnt4 are more specifically PR downstream genes (17–21). Different observations point to potential interactions between ERα and the signal transducer and activator of transcription (STAT) proteins.…”