ERR Gamma: Does an Orphan Nuclear Receptor Link Steroid Hormone Biogenesis to Endocrine Resistance?

Estrogen-related receptor gamma ERR gamma is an orphan nuclear receptor with structural similarities to ER alpha and ER beta 1. In addition to its ability to transactivate classical and imperfect estrogen response elements EREs ERR gamma is a potent activator of transcription from steroidogenic factor-1 SF-1 response elements SF-1REs. Many genes regulated by SF-1REs control key aspects of cholesterol and fatty acid synthesis important not only for generation of the plasma membrane but also for the synthesis of steroid hormones 2. In this study we have investigated whether ERRy expression andlor activity regulates the level of cholesterol in a pair of breast cancer cell lines - one sensitive to endocrine therapy SUM44 and the other resistant to endocrine therapy LCCTam TAM. We found that endocrine-resistant LCCTam TAM cells which overexpress the orphan nuclear receptor ERR gamma contain significantly greater levels of cholesterol than endocrine-sensitive parental SUM44 breast cancer cells and that siRNA-mediated knockdown of ERRy in the resistant TAM cell line significantly reduces cholesterol content. SF-1RE activity is 34old higher in TAM cells as compared to SUM44 cells while expression of an endogenous gene HMGCS2 that contains a consensus SF-1RE is also significantly overexpressed in TAM cells relative to SUM44 cells. Together these findings represent an important enhancement in our knowledge of breast cancer biology and potential therapeutic response.