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

摘要

Much evidence demonstrates that the estrogen receptor (ER) is involved in breast cancer development and progression. We have isolated a novel 97 kDa DEAD box RNA helicase protein (p97), from breast cancer cells, which interacts with the estrogen receptor E and F domains in the presence of either estradiol or trans-hydroxytamoxifen. We have further confirmed the interaction of p97 with ER using both GST-pulldown analysis and a mammalian two-hybrid assay. We have localized a C-terminal (662-864) portion of p97 that specifically interacts with the EF region of the estrogen receptor. In reporter gene assays of transiently transfected cells, p97 decreases the transcriptional activity of agonist-occupied estrogen receptor, progesterone receptor, glucocorticoid receptor, and retinoic acid receptor. However, p97 has no effect on the transcriptional activity of p53 or VP1 6. p97 has intrinsic repression activity on a constitutively active promoter when recruited to it with a Gal4 DNA binding domain. We have identified a small region of p97 that retains this intrinsic repression activity. Trichostatin A, a selective histone deacetylase inhibitor, is able to reverse the repressive activity of p97 on ER, suggesting an involvement of the histone deacetylase complex with p97. Further analysis of this coregulator will allow insight into nuclear receptor function and its role in breast cancer.