Breast cancer is one of the most common cancers in women. Anti-estrogens are now used in the treatment of estrogen-dependent breast cancers. Another related treatment includes the use of aromatase inhibitors, which block the conversion of androgen to estrogen. Recently, the orphan nuclear receptor, liver related homologue 1 (LRH1) has been shown to control gene expression of aromatase in breast cancer tissue. Thus, knowing how LRH1 activity is regulated may provide insights into how aromatase activity is modulated and may, provide new strategies for lowering estrogen levels in breast cancer. My proposed study involves identifying protein partners of LRH1 and how post-translational modifications affect LRH1 activity. For my first aim, I will use a yeast genetic strategy to screen for LRH1 cofactors when LRH1 is bound to its native DNA response element. I will screen cDNAs libraries made from breast cancer cell lines to identify cancer-specific interacting partners ofLRH1. In my second aim, I will determine the role of SUMOylation on LRH1 function since our lab has found that LRH1 interacts with the SUMO-conjugating enzyme UBC9, and the closest homologue of LRH1, steroidogenic factor 1 (SF-1) is SUMOyIated. Ultimately, I want to know if there are selective LRH1 protein partners in breast cancer tissue and how SUMOylation might modulate protein-protein interactions and function of LRH1.
