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HEXIM1 Regulates 17β-Estradiol/Estrogen Receptor-–Mediated Expression of Cyclin D1 in Mammary Cells via Modulation of P-TEFb

¹ Department of Pharmacology, ² Division of Infectious Diseases and Department of Molecular Biology and Microbiology, Case Western Reserve University; and ³ Division of Pediatric Cardiology, Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, Ohio

Requests for reprints: Monica M. Montano, Department of Pharmacology, Case Western Reserve University School of Medicine, H.G. Wood Building W307, 2109 Adelbert Road, Cleveland, OH 44106. Phone: 216-368-3378; Fax: 216-368-3395; E-mail: mxm126{at}po.cwru.edu.

Estrogen receptor (ER) plays a key role in mammary gland development and is implicated in breast cancer through the transcriptional regulation of genes linked to proliferation and apoptosis. We previously reported that hexamethylene bisacetamide inducible protein 1 (HEXIM1) inhibits the activity of ligand-bound ER and bridges a functional interaction between ER and positive transcription elongation factor b (P-TEFb). To examine the consequences of a functional HEXIM1-ER-P-TEFb interaction in vivo, we generated MMTV/HEXIM1 mice that exhibit mammary epithelial-specific and doxycycline-inducible expression of HEXIM1. Increased HEXIM1 expression in the mammary gland decreased estrogen-driven ductal morphogenesis and inhibited the expression of cyclin D1 and serine 2 phosphorylated RNA polymerase II (S2P RNAP II). In addition, increased HEXIM1 expression in MCF-7 cells led to a decrease in estrogen-induced cyclin D1 expression, whereas down-regulation of HEXIM1 expression led to an enhancement of estrogen-induced cyclin D1 expression. Studies on the mechanism of HEXIM1 regulation on estrogen action indicated a decrease in estrogen-stimulated recruitment of ER, P-TEFb, and S2P RNAP II to promoter and coding regions of ER-responsive genes pS2 and CCND1 with increased HEXIM1 expression in MCF-7 cells. Notably, increased HEXIM1 expression decreased only estrogen-induced P-TEFb activity. Whereas there have been previous reports on HEXIM1 inhibition of P-TEFb activity, our studies add a new dimension by showing that E₂/ER is an important regulator of the HEXIM1/P-TEFb functional unit in breast cells. Together, these studies provide novel insight into the role of HEXIM1 and ER in mammary epithelial cell function. [Cancer Res 2008;68(17):7015–24]