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Date of Award
Doctor of Philosophy (PhD)
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.
Chair and Committee
Kendall J. Blumer, John R. Edwards, William E. Gillanders, Jason C. Mills,
Searleman, Adam, "Mechanisms of HER2-Driven Transformation of Mammary Epithelium" (2016). Arts & Sciences Electronic Theses and Dissertations. 744.
Available for download on Friday, May 15, 2116