Abstract This is the revision of the year 25-29 competitive renewal of the UNC Breast Cancer SPORE, one of the original 1992 SPOREs, which has contributed key findings in breast cancer translational research in minority disparities, genomic analysis, molecular subtyping and therapeutic resistance, while advancing new technology and developing junior faculty into translational research leaders. The constant since 1992 is a population- based, biospecimen-rich, epidemiological and clinical infrastructure, the Carolina Breast Cancer Study (CBCS). CBCS Phase 3 has finished accrual of an additional 3,000 cases and embarked on a ten-year follow- up with treatment, adherence, and outcome data. CBCS oversamples African Americans (AA) and patients aged 50 or younger to provide one of the largest population-based studies of age and race disparities. CBCS has made seminal contributions to our understanding of triple negative breast cancer (TNBC) and other breast cancer subtypes in North Carolina?s AA population with over 150 papers published. For example, our SPORE has published articles characterizing Basal-like TNBC that have been cited over 23,000 times. With substantial institutional investment, the UNC SPORE: i) Incorporates new technology and novel methods; ii) Develops infrastructure that provides new directions; and iii) Promotes career advancement for junior and mid-level faculty from the population, basic and clinical sciences. In the last 5 years, the CEP and DRP produced seven Komen Catalyst Awardees. The CEP brought 13 new faculty to the SPORE, 5 of them women and 3 minorities. The DRP funded collaborative projects between: engineers and clinicians to produce unique instruments and methods for early detection; immunologists and geneticists to study breast cancer immune infiltrates and responses; and outcomes researchers, clinicians and programmers to create new databases to study breast cancer care delivery in North Carolina. With EAB and Executive Committee input, the multi-PIs Chuck Perou and Shelley Earp with clinician co-lead Lisa Carey selected 4 projects for this revised renewal, focusing on minority disparities, developing a new understanding of resistance to immuno- and chemotherapies, and developing novel, clinically practical, predictive biomarkers. Project #1 ? The Carolina Breast Cancer Study (Troester, PhD and Carey, MD, MSc) will explore biologic and genomic differences in AA (1500) and white (1500) tumor specimens relating those to multiple patient-level parameters. The other projects are: Project #2 Inflammatory Signaling and ER+ Breast Cancer Therapeutic Resistance (Franco, PhD, Baldwin, PhD and Dees, MD, MSc); #3 Development of Chemotherapy and Immunotherapy Biomarkers for TNBC (Perou, PhD and Carey, MD, MSc) and #4 Therapeutic Approaches to the Adaptive Chromatin Remodeling that Underlies Resistance (Johnson, PhD and Earp, MD).