BME-IBSC PhD Preliminary Exam Announcement for Brenna Vaughn (L. Solorio, advisor) Everyone is invited to attend the public presentation beginning at 3:30 PM. Title: Transglutaminase-2 Enables Cluster-Mediated Resistance in HER2-Overexpressing Breast Cancer Cells Date: April 16, 2024 Time: 3:30 PM Location: MJIS 2001 Committee: Luis Solorio, Chair; Leopold N. Green; Sherry L. Harbin; Michael K. Wendt Abstract: Breast cancer has killed more than 18 in 100,000 women per year in the United Sates for the past 20 years. Approximately 20-25% of newly diagnosed tumors are human epidermal growth factor receptor (HER2)-positive. HER2-positive tumors carry an increased risk of metastasis in which the disease spreads to other parts of the body. Early or metastatic HER2-positive breast cancer can be treated with the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1). However, resistance to T-DM1 and disease progression is common. In some metastatic lesions, Transglutaminase 2 (TG2), an enzyme that catalyzes crosslinking reactions, is upregulated. We demonstrate the ability of HER2-transformed human mammary epithelial cells (HME2) overexpressing TG2 to gain resistance to T-DM1 in vitro. We additionally show that T-DM1 preserves an epithelial cell population with accelerated growth on fibronectin coated coverslips. Furthermore, we demonstrate a cluster size-based pattern of therapeutic resistance. We utilize mouse models of lung metastases and mammary tumors to generate models of resistance alongside in vitro applications. This work demonstrates the ability of HER2- transformed human mammary epithelial cell clusters to form T-DM1 surviving proliferative epithelial cell populations.