Breast cancer is the most common invasive cancer among women worldwide and the second leading cause of cancer mortality in women. However, breast cancer is not a single disease, but rather a heterogeneous group of cancers with a variety of molecular drivers regulating tumor development, progression, and response to therapy. Thus, a central goal in breast cancer research has been to identify the key genetic alterations defining specific subsets of this cancer, thereby providing an opportunity to develop targeted therapies against the specific proteins affected by these alterations. This strategy has been realized, in one instance, with the identification of ERBB2 (HER2) gene amplification as an oncogenic driver for ~20% of breast cancers, and has led to the production of therapeutic monoclonal antibodies (including trastuzumab, pertuzumab, T-DM1, and T-DXd) for treatment of tumors harboring this amplification. The impact of these antibody-based therapeutics has been transformative, dramatically increasing survival of patients with HER2-positive breast cancer. Nevertheless, many patients with HER2-positive breast cancer are initially resistant to this therapy or develop resistance with time, so that now a major challenge to the field is to understand the mechanisms driving this treatment resistance and to develop new approaches to target these resistant cancers. This research project focuses on p95HER2, a truncated form of HER2 that is produced via the use of an alternative translation initiation site within the HER2 mRNA, corresponding to Met611 in the full-length HER2 protein. The p95HER2 protein lacks nearly the entire extracellular domain and therefore cannot be recognized by any of the HER2-directed therapeutic antibodies in clinical use, yet retains oncogenic signaling properties. As such, upregulation of p95HER2 represents one mechanism for the development of therapy resistance. In addition, our work demonstrates that p95HER2 expression in breast cancer cells drives a distinct set of signaling pathways, different from those driven by the full-length HER2 oncoprotein, which exert unique effects on the tumor microenvironment. Therefore, we speculate that HER2-positive breast cancers that co-express the p95HER2 variant are fundamentally different with regard to how they interact with the tumor microenvironment and may respond differently to therapeutics that engage anti-tumor immunity. The overarching objectives of this project are to fully understand the impact of p95HER2 on cells of the tumor microenvironment, specifically with regard to the tumor immune response.