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

Abstract

Estrogen receptor A (ERA) 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 ERA and bridges a functional interaction between ERA and positive transcription elongation factor b (P-TEFb). To examine the consequences of a functional HEXIM1-ERA-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 ERA, P-TEFb, and S2P RNAP II to promoter and coding regions of ERA-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 E 2 /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 ERA in mammary epithelial cell function. [Cancer Res 2008;68(17):7015-24]

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…A recent report shows that hexamethylene bis-acetamide inducible protein 1 (HEXIM1) inhibits ERα-mediated expression of cyclin D1 in mammary cells by curbing the recruitment of the transcription factor complex comprised of ERα, positive transcription elongation factor b (P-TEFb), and serine 2-phosphorylated RNA polymer-ase II onto CCDN1 promoter. This implies that HEXIM1 is a critical regulator of E2-induced cyclin D1 expression in breast cancer cells during tumor invasion and metastasis [53].…”

HER2/ECD Serumwerte bei Stadium I und II Brustkrebs – brauchen wir niedrigere Grenzwerte?

“…p53), as well as expression of antiapoptotic (Bad/Bcl-2) and loss of function of proapoptotic genes lead to uncontrolled cell growth and division, and after gaining additional genome damage with consequent cell immortalization breast cancer develops [1][2][3][4][5][6][7][8]. Estrogens and progesterone induce expression of cyclin D1 and c-myc as well as Bad/Bcl-2, which is proposed mechanism of hormonedependent breast cancer development, seen in about 80% of breast cancer patients [9,10]. In the remaining 20% of patients, the proposed mechanism is overexpression of epidermal growth factor (EGF) receptor amplifi er, i.e.…”

CLP-1 associates with MyoD and HDAC to restore skeletal muscle cell regeneration

“…HEXIM1 expression has been reported to correlate with estrogen receptor-inducible cyclin D1 protein expression and binding to the E 2 -responsive region on the cyclin D1 promoter (Ogba et al, 2008). Using ChIP assay, we localized CLP-1 and its associated proteins, MyoD and HDACs, on the cyclin D1 promoter in C2C12 cells, which occurs preferentially in the differentiation stage.…”

“…We examined association of this inhibitory complex to the cyclin D1 promoter because cyclin D1 is a cell cycle regulatory protein whose levels were reported to change in response to HEXIM1 (Ogba et al, 2008). Cyclin D1 protein in C2C12 cells is expressed only under growth conditions, as shown by western blotting (Fig.…”