The Dana-Farber/Harvard Cancer Center (DF/HCC) SPORE in Breast Cancer seeks to improve the understanding and treatment of breast cancer with an integrated, innovative, and highly translational approach. The application consists of four Projects and four Cores. Project 1 brings together strong basic- and population-science investigators. It builds upon promising clues about androgen receptor (AR) signaling and will investigate the role of signaling through the AR and the development and progression of breast cancer The investigators will develop a novel approach to characterizing AR signaling as part of this effort. Project 2 uses state-of-the-art genetically engineered mouse models and a cutting edge clinical trial to evaluate resistance mechanisms in HER2+ breast cancer. It seeks to overcome this resistance by further interrogating the PI3 kinase pathway, and will evaluate sensitivity and resistance to PI3 kinase inhibitors. Project 3 shifts current paradigms by the development of approaches that will sensitize BRCA-proficient triple negative breast cancer cells to PARP inhibition. The Project is built upon a solid background including cell lines, patien-derived orthotopic xenograft models, and early phase clinical trials. Project 4 explores a new avenue in drug development assessing the mechanisms of action of BET/bromodomain inhibitors for the treatment of triple negative breast cancer. A strong pre-clinical phase is followed by a clinical trial with ability to understand how genomic modulation impacts the outcome of patients diagnosed with triple negative breast cancer. Each Project will contribute substantially to the understanding of the biology of breast cancer. The preclinical and clinical findings from these projects will stimulate further research and could have significant clinical impact. Our SPORE proposal uses Cores to support the Projects, as well as other researchers in the DF/HCC community. Core A is the epicenter of scientific, fiscal and administrative oversight. It will lead efforts in planning and communication. It also houses the Patient Advocacy Committee arid will oversee the Developmental Research Program (DRP) and the Career Development Program (CDP) awards. Core B, Biostatistics and Computational Biology provides specialized expertise in biostatistics and management of genomic data. Core C, Clinical Trials Core will oversee all clinical trials associated with the Breast SPORE. It will review all protocol, coordinate the activation process, monitor the conduct of clinical studies and facilitate biopsy-intensive studies in collaboration with Core D. Core D, Tissue and Pathology Core will maintain tissue/blood repositories for the SPORE Projects and, to some extent, for investigators outside of the SPORE. This Core will also provide pathology services that are critical to many of the translational research aims in Projects. The DF/HCC SPORE in Breast Cancer is comprised of a team of top-notch basic, translational, and clinical investigators who are led by an experienced and effective Program Director and Senior Leadership Team. The DF/HCC SPORE is poised to make substantial contributions over the next five years and beyond.