UICC World Cancer Congress 2006

Objective: Breast cancer is one of the leading causes of death among women. Despite the fact that estrogen antagonists are widely employed in the treatment of hormone-responsive breast cancers, a major problem encountered is the inevitable development of resistance. The molecular mechanisms by which these compounds inhibit cellular proliferation are not fully defined which limits the development of improved therapy. We therefore studied the molecular mechanisms underlying estrogen antagonist-induced growth repression.

Methods: The estrogen receptor (ER) is a hormone-activated transcription factor that mediates the stimulatory effects of estrogens and the inhibitory effects of anti-estrogens, such as tamoxifen. We recently found that prohibitin, a potential tumor suppressor, is required for estrogen antagonist-induced growth suppression, a process which is ER-dependent. We therefore studied the potential function of prohibitin and its co-repressors, Brg1 and Brm, in the modulation of ER in response to estrogen and its antagonists using chromatin immuno-precipitation, immuno-precipitation, immuno blot analysis.

Results: Brg1 is required for activation of ER-mediated transcription. We report here that Brg-1, and related Brm, also participate in the repression of ER-mediated transcription, by differential coordination with BAF155, BAF170, HDAC1, p300 and prohibitin. Although both estrogen and its antagonists induce the recruitment of Brg1/Brm to ER-responsive promoters, the molecular mechanisms of these recruitments differ, involving different BAFs and modulators of histone acetylation. Thus, the same chromatin remodeling molecules, Brg1 and Brm, are differentially required for both activation and suppression of ER activity. These studies thus provide new targets for future multidisciplinary therapeutic approaches.