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An Estrogen Receptor-Selective Coactivator: A Potential Regulator of Tamoxifen Effectiveness in Breast Cancer Treatment and Prevention

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Annual summary rept. 1 Sep 1999-31 Aug 2000

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There is a strong correlation between the presence of the estrogen receptor protein in breast tumors and their likelihood of response to endocrine therapy. We aim to better understand estrogen receptor physiology and its role in tamoxifen effectiveness. We have cloned a novel protein that interacts with the estrogen receptor in a ligand dependent manner. Having isolated the full-length clone, we find that this protein represses, rather than enhances, the activity of the estrogen receptor. This 97 kDa novel protein decreases the magnitude of estrogen receptor transcriptional activity by up to 90 in reporter gene assays of transfected breast cancer cell lines. This protein has intrinsic repression activity on a constitutively active SV40 promoter when recruited to it. We also show that the HDAC blocking drug Trichostatin A also reverses the repressive activity of this protein on the estrogen receptor. Thus, this protein may work by histone deacetylation. Further understanding of the mechanism of repression by this protein will help elucidate its role in estrogen receptor action in breast cancer cells as it may assist in repressing estrogen receptor stimulation of breast tumors and enhance the effectiveness of tamoxifen as an antiestrogen.

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  • Medicine and Medical Research

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