Estrogen-related Receptor alpha (ERR (alpha))-Coactivator Interactions as Targets for Discovery of New Anti-breast Cancer Therapeutics.

摘要

At the time of diagnosis, 30% of all breast tumors grow independently of hormone. These cancers are unlikely to respond to currently available hormonal therapies. Of the 70% of breast tumors that do depend on hormone for growth, only about half of these patients will respond to hormonal therapies, such as aromatase inhibitors and the selective estrogen receptor modulator (SERM) tamoxifen. However, drug resistance often develops after long term treatment as the tumor progresses to a hormone-independent state. There is a great need for novel therapies for breast cancer. Estrogen-related receptor alpha (ERR ) is a protein that is structurally and functionally similar to estrogen receptor alpha (ER ), the primary focus of hormonal therapy for breast cancers. Like ER , ERR can bind to estrogen-response elements (EREs) present in certain gene promoters and, by interacting with transcriptional co-activators, activate transcription. But unlike ER , ERR binds neither estrogen nor tamoxifen; in fact, all data indicate that ERR can act independently of hormones. Recent statistical data from a retrospective clinical study indicate that over-expression of ERR correlates with breast cancer recurrence and adverse clinical outcome (Suzuki et al., 2004). In addition, using quantitative RT-PCR analysis in clinical primary breast cancers, expression of ERR is correlated with ER -negative and HER2-positive tumors status (Ariazi et al., 2002). These observations strongly suggest that ERR plays an important role in the progression of a significant subset of breast cancers.