Endocrine-based therapies have been very effective at reducing mortality but ~ 25% of patients will progress and only 30% of those with metastatic disease will respond. Therefore, there is a tremendous need to identify the mechanisms that drive estrogen receptor alpha positive (ER+) breast cancer and promote invasion. We found that ERα sequesters activated RSK2, a Ser/Thr protein kinase, into the nucleus to promote neoplastic transformation and invasive tumor growth. Anti-estrogens disrupted the RSK2/ERα complex, driving RSK2 into the cytoplasm with corresponding reduced tumor growth. We hypothesize that failure to disrupt the interaction between RSK2 and ERα with endocrine-based therapy leads to metastasis. In support of this hypothesis the RSK2 gene signature stratifies patients with invasive breast cancer based on positivity for ERα. The mechanism by which RSK2 promotes ER+ breast cancer progression will be identified and evaluated in patient-derived xenografts (aim 1). We will test whether RSK2 in complex with a tamoxifen- resistant ERα mutant drives metastasis using engineered ER+ breast lines (aim 2). RSK inhibitors based on the parent compound, SL0101, will be generated to identify compounds with improved in vivo efficacy to inhibit ER+ tumor growth and metastasis (aim 3). Data generated in this proposal will be analyzed using the appropriate statistics for end point and longitudinal analysis. The successful development of a RSK inhibitor could dramatically improve outcomes for patients with ER+ metastatic breast cancer.