Open Access Dissertation
Date of Award
Julie L. Boerner
Breast cancer can be divided into genetic sub-types including luminal, HER2+, and basal-type. With the introduction of targeted therapies against estrogen receptor and HER2 receptor mortality rates of American women with breast cancer have declined. Unfortunately, basal-type breast cancers, which have the worst clinical outcome, do not express estrogen receptor or HER2, and as such, have no targeted therapeutic option. The epidermal growth factor receptor is an attractive target for therapeutics in basal-type breast cancer, as it is over-expressed in 60% of these cases. Also, over-expression of EGFR correlates with poor patient prognosis. Unfortunately, inhibitors of EGFR have shown little clinical efficacy in basal-type breast cancers. We have utilized basal-type breast cancer cell lines to determine a potential mechanism of resistance to EGFR-targeted small molecule tyrosine kinase inhibitors (TKIs). Specifically, we have shown that EGFR localizes to discrete membrane microdomains (lipid rafts) in cell lines that are resistant to EGFR TKI-induced growth inhibition. Depletion of lipid rafts via cholesterol reduction results in sensitivity of EGFR TKI resistant breast cancer cell lines to the EGFR TKI gefitinib. Importantly, the effects of cholesterol lowering drugs and EGFR TKI in combination were synergistic. We have shown that the non-receptor tyrosine kinase c-Src, which is co-over-expressed with EGFR in a subset of breast tumors, also localizes to lipid rafts in the SUM159 breast cancer cell line. In this model system, c-Src kinase inhibition results in synergistically decreased cell viability in combination with EGFR tyrosine kinase inhibition. c-Src kinase inhibition and cholesterol depletion are additive, results that suggest these two inhibitors work within the same pathway. Indeed, treatment with either cholesterol lowering drugs or c-Src kinase inhibitors results in decreased EGFR-kinase independent Akt phosphorylation. Thus, lipid rafts may provide a platform whereby EGFR and c-Src interact to promote Akt signaling in the absence of EGFR kinase activity. These results suggest, for the first time, that lipid rafts are involved in EGFR-kinase independent signaling, and that depletion of these rafts may work in combination with EGFR tyrosine kinase inhibition to decrease breast cancer cell growth.
Irwin, Mary Elizabeth, "A Role For Lipid Rafts In Egfr Tki Resistance In Breast Cancer" (2010). Wayne State University Dissertations. 61.