Mechanisms of HER2-Driven Transformation of Mammary Epithelium

In 20-30% of breast cancers, high expression of the HER2 proto-oncogene induces constitutive activation and is associated with poor prognosis. While HER2-targeted therapy has greatly improved the prognosis of these patients, resistance remains a major clinical problem. Critical insights on how to predict, prevent, or overcome resistance might be derived from a better understanding of the mechanisms of HER2-mediated transformation in breast epithelium. HER2 is an ErbB family co-receptor tyrosine kinase that is centrally embedded in a complex signaling network that interacts with many known signaling modules implicated in cancer. These include activation of MAPK cascades, PLC, aPKC and PI3-K/AKT through dimerization with the members of the ErbB family, and extensive crosstalk with signaling pathways such as TGF, mTOR, GPCRs, NOTCH, and NF-B. The complexity of the HER2 signaling network has obfuscated efforts to understand how HER2 over-activation contributes to tumorigenesis. In this thesis, we present the first phosphoproteomic analysis of HER2-driven breast cancer, and identify potential therapeutic targets with known inhibitors. We identify activating HER2 mutations in breast cancers that lack HER2 overexpression. Oncogenic HER2 mutations induced an epithelial-mesenchymal transition in 3D culture conditions dependent on ZEB1 upregulation via signaling from the MAPK, NF-B, and SRC/STAT3 pathways. Finally, we characterize the early neoplastic lesions in a mouse model of HER2-driven breast cancer, and find that this model does not recapitulate key aspects of the microenvironment of pre-invasive human breast cancer. In summary, we present data that elucidate the key signaling pathways activated by oncogenic HER2 mutations in mammary epithelium