Project Summary Triple Negative Breast Cancer (TNBC) is an aggressive malignancy with a poor prognosis that accounts for 10- 20% of breast cancer cases worldwide. Tumor resistance to chemotherapy is a major obstacle facing patients with TNBCs, as TNBCs lack conventional druggable targets and patients rely on chemotherapy as the main treatment option. Intra-tumoral heterogeneity and tumor cell plasticity are thought to contribute to resistance to chemotherapy. Basal-like breast cancer (BLBC) is a molecular subtype that makes up ~70% of TNBCs, and is characterized by high heterogeneity and genetically diverse tumor cells. The mechanism by which BLBC tumor cells develop resistance to chemotherapy is poorly understood. I hypothesize that plasticity between tumor cell phenotypic states, specifically basal-like and mesenchymal states, leads to changes in tumor sensitivity to chemotherapy. This work aims to identify the genetic regulators of plasticity between subpopulations of BLBCs and to test whether targeted agents blocking or initiating this plasticity can lead to changes in tumor chemo-sensitivity. To do this, my first aim is to identify the functional and genomic characteristics of distinct cellular subpopulations in BLBCs by flow cytometry and single cell RNA-sequencing (scRNA-seq), using murine and human TNBC models in vivo. I will use gene expression and network analyses to identify possible genetic regulators of each subpopulation, and test these empirically using CRISPR knockouts. In the second aim, I plan to test whether chromatin remodeling inhibitors are able to block EMT in BLBC tumors and thereby increase tumor sensitivity to chemotherapy. This work is expected to identify potential inherent and therapy-induced regulators of tumor plasticity, which could have therapeutic implications in developing improved treatment regimens for patients with chemo-resistant TNBCs.