Inhibition of ERK signaling for treatment of ERRα positive TNBC.

Breast cancer is the second leading cause of cancer-related deaths in women and triple-negative breast cancer (TNBC), in particular, is an aggressive and highly metastatic type of breast cancer that does not respond to established targeted therapies and is associated with poor prognosis and worse survival. Previous studies identified a subgroup of triple-negative breast cancer patients with high expression of estrogen related receptor alpha (ERRα) that has better prognosis when treated with tamoxifen. We therefore set out to identify common targets of tamoxifen and ERRα in the context of TNBC using phosphoproteomic analysis. In this study, we discovered that phosphorylation of mitogen-activated protein kinase 1 (MAPK1) is regulated by tamoxifen as well as ERRα. Additionally, we showed that inhibition of MAPK signaling together with the use of a selective ERRα inverse agonist, XCT-790, leads to a significant upregulation of apoptosis and paves way for the therapeutic use of MAPK inhibitors for treatment of ERRα expressing TNBC.