Estrogen receptor alpha (hereafter called ER) is believed to be the main driver of most (>75%) breast cancers in women. Once bound by estrogen, ER works by “turning on” proliferation genes that are required for tumor cell growth. Tamoxifen is frequently used to treat ER+ breast cancer because this drug outcompetes estrogen for ER binding and causes the proliferation genes to be “turned off” leading to tumor cell death. Unfortunately, most women that receive tamoxifen therapy eventually become resistant to tamoxifen and their tumors begin to grow again. Exactly how tamoxifen resistance occurs remains unclear and this lack of understanding remains a major barrier  that must be overcome to improve and extend the lives of ER+ breast cancer patients. One potential reason that these ER+ tumor cells become tamoxifen-resistant is that long-term tamoxifen treatment eventually causes the overproduction of a set of ER-associated proteins called co-activators. These co-activators can then convert tamoxifen from an antagonist to an agonist; meaning in the presence of elevated levels of these co-activators, tamoxifen somehow undergoes a switch and begins to turn ER target genes on instead of turning them off. The main goal of this application is to use cutting-edge genome-wide technologies and mouse models of breast cancer to formally test the requirement of a newly identified ER co-activator for estrogen signaling and tamoxifen resistance. Successful completion of our proposed studies will advance our understanding of the precise mechanisms by which estrogen and tamoxifen regulate the expression of ER target genes in breast cancer cells and how the antagonist-to-agonist “tamoxifen switch” occurs. Additionally, our studies will also define new drug candidates for the treatment of tamoxifen sensitive and resistant ER+ breast cancer.