Steroid receptor coacfivator-3/amplified in breast cancer-1 (SRC-3/AIB1) is frequently overexpressed in breast carcinomas and can promote cell growth and resistance to endocrine therapies. In breast carcinomas overexpressing SRC-3, especially when in combination with activated HER2 signaling, the selective ER modulator (SERM) tamoxifen functions as an ER agonist. ER+/HER2+ tumors have a very poor response to tamoxifen treatment if SRC-3 is also overexpressed. Experimental targeting of SRC-3 can both a) augment the anti-estrogenic and anti-proliferative activity of tamoxifen in hormone-naive breast cancer cell lines, and b) restore the anti-estrogenic and anti-proliferative activity of tamoxifen in refractory breast cancer cell lines. Therefore, targeting SRC-3 expression and/or function is expected to enhance the activity of first-line conventional therapy and restore sensitivity in treatment-refractory breast cancer. Unfortunately, up to this point, SRC-3 has been considered "undruggable" because it lacks a natural ligand-binding site that can be inhibited by small molecule compounds and protein:protein interacfions are difficult to disrupt. Importanfiy, the stability and activity of the SRC-3 protein are strongly regulated via its post-translational modificafion (PTM) by upstream kinase signaling networks, including protein kinase C (PKC). PKC family members can phosphorylate and protect SRC-3 from proteasome-mediated degradation. Given the critical role of SRC-3 in breast cancer and the lack of FDA-approved SRC-3 targeting agents, this proposal represents an innovafive hypothesis-driven approach, based on key basic research and robust preclinical evidence, to establish PKC SMls as first-in-class inhibitors of SRC-3 expression and function and as targeted therapies for use in combination with conventional agents for ER+ breast cancer. Preliminary studies demonstrate that PKC inhibitors (including agents that have been well-tolerated in clinical trials in other diseases) can, at clinically achievable and tolerated concentrafions, decrease SRC-3 protein expression, exert anticancer activity in SRC-3-overexpressing cell lines, enhance the anticancer activity of endocrine therapy in sensifive cells lines, and restore sensitivity to endocrine therapy in resistant breast cancer cell lines and xenografts.