Role of Estrogen-Related Receptor Alpha in Steroidogenesis in the Breast

摘要

This project has focused on the potential role of Estrogen-Related Receptor alpha (ERRalpha) in regulating steroidogenesis. ERRalpha is an orphan nuclear receptor closely related to the Estrogen Receptors (ERs), and while its expression correlates with unfavorable biomarkers and poor prognosis for breast cancer, its function in breast cancer biology is not known. This project was initiated because we observed that a primary coactivator of ERRalpha, PGC- 1alpha, induces hepatic gene expression of the initial enzymes in steroidogenesis, including steroidogenic acute regulatory protein (StAR), cytochrome p45011A1 (CYP11A1), cytochrome p45017A1 (CYP17A1), and aromatase (CYP19). We endeavored to characterize ERRalpha's role in regulating the expression of these enzymes in the breast, since increasing evidence points to local production of steroids as a significant source of estrogens in breast cancer, particularly in postmenopausal women (Simpson, 2003). We proposed to examine whether these steroidogenic enzymes are regulated by the ERRalpha/PGC- 1alpha pathway in breast cancer cell lines, to determine which ERRalpha cofactors are present in breast, and to examine regulation of steroidogenic enzymes through ERRalpha by other cofactors.