HEXIM1 regulates 17beta-estradiol/estrogen receptor-alpha-mediated expression of cyclin D1 in mammary cells via modulation of P-TEFb.

Estrogen receptor alpha (ERalpha) 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 ERalpha and bridges a functional interaction between ERalpha and positive transcription elongation factor b (P-TEFb). To examine the consequences of a functional HEXIM1-ERalpha-P-TEFb interaction in vivo, we generated MMTV/HEXIM1 mice that exhibit mammary epithelial-specific and doxycycline-inducible expression of HEXIM1.

Differential induction of quinone reductase by phytoestrogens and protection against oestrogen-induced DNA damage.

Quinone reductase (QR) is a phase II detoxification enzyme that plays an important role in detoxifying quinones and may help maintain the antioxidant function of the cell. We have previously observed that QR is up-regulated by anti-oestrogens, but not oestrogen, in breast cancer cells via ERbeta (oestrogen receptor beta) transactivation. Such QR induction appears to protect breast cells against oestrogen-induced oxidative DNA damage, most likely by reducing reactive oestrogen metabolites termed catecholestrogen-quinones back to the hydroxy-catecholestrogens which may be conjugated.