Role of ERalpha-ERRalpha Heterodimers in Tamoxifen-Resistant Breast Cancers.

摘要

We began to test the hypothesis that ERR; may play a major role in the etiology or progression of tamoxifen-resistant breast cancers, doing so by heterodimerizing with ERalpha and, thus, enabling transcription, despite the presence of tamoxifen, of some key estrogen responsive element-regulated genes involved in growth control of breast cells. Supporting this hypothesis, we identified a breast cancer cell line, MCF-7/HER2-18, that regains sensitivity to killing by tamoxifen when treated with XCT790, a drug that specifically knocks down ERRalpha protein levels. We also identified an ERRalpha specific monoclonal antibody that can be used in ChIP-seq experiments. We used it to note putative sites in the human genome where ERalpha-ERRalpha heterodimers may bind in the presence of estrogens and, presumably, tamoxifen to regulate expression of genes that could play key roles in the development of tamoxifen- resistant breast cancer. Our findings provide additional evidence that drugs that specifically disrupt formation of ERalpha-ERRalpha heterodimers may serve as a novel, specific therapeutics for treating patients with tamoxifenresistant breast cancer. More generally, these studies suggest that patients with tamoxifen-resistant breast cancers may derive more therapeutic benefit from treatment with new or existing drugs (e.g., Herceptin) that affect the activities of ERRalpha than from ERalpha-targeted therapeutics.