Progesterone Receptor as a transcriptional repressor regulates breast cancer growth

CECILIA J PROIETTI

Congreso; LXII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2017

Progesterone receptor (PR) is a critical mediator of mammary gland development and contributes to breast cancer progression. In its classical mechanism of action PR associates with specific progesterone response elements (PREs) on chromatin. DNA-bound PR recruits transcriptional coactivators and associated cofactors, which modify the local chromatin structure and facilitate transcriptional activation, resulting in activation or repression of PR target genes. PR may also alter gene expression nonclassically, where the receptor tethers to other transcription factors bound to DNA. In addition to its direct transcriptional effects, PR activates signal transduction pathways in breast cancer cells through a rapid or nongenomic mechanism. PR transcriptional outcome is affected by complex interactions between PR and other regulatory factors which results in different PR cistromes. Till present more attention and study has been devoted to gene activation compared to gene repression mediated by hormones, in particular, progestins. In fact, gene repression is poorly understood, with some authors even considering repression as a secondary effect of activation. In the present study, we addressed a poorly explored PR function: its capacity to repress gene expression. In this study, we demonstrate that progestin-activated progesterone receptor reduces the expression of the master transcription factor GATA3. GATA3 is involved in mammary gland development and is crucial for the maintenance of the differentiated status of luminal epithelial cells. The role of GATA3 in breast cancer as a tumor suppressor has been established, although insights into the mechanism of GATA3 expression loss are still required.In the present work, we show that ligand-activated PR modulates GATA3 expression through regulation at the transcriptional and post-translational levels in breast cancer cells. In the former mechanism, the histone methyltransferase enhancer of zeste homolog 2 is co-recruited with activated PR to a putative progesterone response element in the GATA3 proximal promoter, increasing H3K27me3 levels and inducing chromatin compaction, resulting in decreased GATA3 mRNA levels. This transcriptional regulation is coupled with increased GATA3 protein turnover through progestin-induced GATA3 phosphorylation at serine 308 followed by 26S proteasome-mediated degradation. Both molecular mechanisms converge to accomplish decreased GATA3 expression levels in breast cancer cells upon PR activation. In addition, we demonstrate that decreased GATA3 levels are required for progestin-induced upregulation of cyclin A2, which mediates the G1 to S phase transition of the cell cycle and was reported to be associated with poor prognosis in breast cancer. Finally, we show that downregulation of GATA3 is required for progestin stimulation of both in vitro cell proliferation and in vivo tumor growth.