Gene expression-based approaches to breast cancer are largely for prognostication, not prediction of individual drug responses. Furthermore, there are still no clinically validated somatic mutation-based approaches in breast cancer management based on next generation DNA sequencing (NGS). A major obstacle to progress in NGS-based diagnostics is a fundamental one: we poorly understand how complex cancer somatic genomes drive clinical phenotypes and drug vulnerabilities. Key issues such as therapeutic resistance, the contribution of the tumor microenvironment and the metastatic process belie single gene/mutation explanations. The new field of proteogenomics provides an opportunity to generate new insights by melding the complexity of cancer genomics with cancer proteomics to more completely understand how somatic genomes activate aberrant signal transduction events that drive cancer pathogenesis. To this end, we have formed a multi-institutional, multi-omics center to engage in collaborative studies under the aegis of the NCI-CPTAC PTRC initiative. Our core builds upon ongoing collaborations between the highly experienced and innovative teams at Baylor College of Medicine and the Broad Institute with complementary strengths in cancer genomics, precision diagnostics, proteogenomic technologies and decades of experience in breast cancer research. Our proposal leverages state-of-the-art quantitative discovery proteomics and phosphoproteomics as well as targeted assays to measure the kinome and chromatin modifications. These sensitive and reproducible pipelines will be used to analyze preclinical models, well-annotated cohorts and clinical trial samples in an iterative design. A robust proteogenomics pipeline developed by our group will be used to analyze and visualize the data. These analyses, together with the primary data generated by this multidisciplinary proposal will be made rapidly available to the scientific community. While the FOA envisioned that only targeted approaches could be applicable in the Clinical Research Arm, it did not anticipate the major advances already well underway in discovery proteomics. We show that the global, discovery-based proteome and phosphoproteome pipeline we have developed is already applicable to biopsy-scale tumor samples, providing deep and broad quantitative coverage of the proteome and phosphoproteome with excellent reproducibility and robustness. This key conceptual and practical advance enables us to employ discovery and targeted approaches in both Preclinical and Clinical arms thereby greatly increasing the power of our proposed studies to generate impactful insight into the causes of breast cancer mortality. We postulate that this integrated approach will provide new understanding of the biology of response and resistance to chemotherapeutics, sounder therapeutic hypotheses and identify more accurate predictive biomarkers for drug resistance and treatment selection that could be developed and deployed as clinical tests.