Highlighting Progesterone (PR) Receptor Repressive Transcriptional Skills: GATA3 Is Downregulated by PR Activation To Induce Breast Cancer Cell Growth

CECILIA J PROIETTI

San Diego

Congreso; 2015 Endocrine Society Annual Meeting; 2015

The master transcription factor GATA3 is involved in mammary gland development and is crucial for maintenance of the differentiated status of luminal epithelial cells. The role of GATA3 as tumor suppressor in breast cancer has been established, with increased GATA3 expression correlating with good prognosis in breast cancer patients. However, insights into the mechanism of GATA3 expression loss during tumor progression are still required. In the present work, we demonstrate that progestin-activated PR produces GATA3 mRNA downregulation. This modulation 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. Finally, we demonstrate that GATA3 downregulation is required for progestin stimulation of both in vitro cell proliferation and for in vivo tumor growth.