While it is widely accepted that the risk of developing breast cancer is directly related to one's lifetime exposure to estrogen, the precise role of estrogen in the initiation and progression of breast cancer has yet to be determined. We reported that estrogens downregulate the expression of the transcription factor Hexamethylene-bis-acetamide-inducible protein 1 (HEXIM1), and HEXIM1, in turn, inhibits Estrogen Receptor (ER?) transcriptional activity. Our mechanistic studies suggest that HEXIM1 mediates a novel link between ER? and transcription elongation factor, cyclin T1. HEXIM1 inhibits the co-recruitment of ER? and cyclin T1 to the promoter region of ER? target genes. As a result, HEXIM1 prevents ER?-mediated transcriptional elongation in breast epithelial cells. A mouse model created in my laboratory whereby HEXIM1 overexpression was targeted to the mammary gland produced results consistent with HEXIM1 inhibition of cyclin D1 and mammary epithelial cell proliferation via repression of cyclin T1. While the vast majority of the literature on HEXIM1 mechanism of action has focused on its functional interaction with the elongation machinery, our studies support biological actions of HEXIM1 that are not dependent upon its ability to interact with cyclin T1. This conclusion is based on our studies using a mutant HEXIM11-312 protein that is able to inhibit cyclin T1. We now report that this mutant HEXIM1 protein is able to actively promote mammary tumorigenesis. Together our results indicate that HEXIM1 plays a critical role in estrogen-regulated breast cancer. Based upon our findings, we hypothesize that modulation by HEXIM1 of estrogen-regulated transcription plays an important role in mammary gland development/tumorigenesis. The main specific aims of the proposed studies are to determine: (1) Does the recruitment of HEXIM1 and the inhibition of ER?-regulated transcriptional elongation play critical roles in the repressive effects of tamoxifen-liganded ER?? (2) What is the relative contribution of ER?-HEXIM1 functional interaction to HEXIM1 regulated transcriptional networks? (3) Will inactivation of HEXIM1 lead to mammary tumorigenesis that can be modulated by estrogens?
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