miR-200c control of breast and endometrial cancer progression

Breast cancer constitutes 30% of cancer cases diagnosed among American women, and endometrial cancer accounts for 6% per annum. Together, these are responsible for the deaths of almost 80,000 American women. Since both breast and endometrial cancer are largely curable if detected while still localized, metastatic disease is the cause of these mortalities. Although the etiology and clinical presentation of these two diseases are quite different, the more metastatic forms of both carcinomas display characteristics of having undergone an epithelial to mesenchymal transition and have dramatically lower levels of miR-200c than the less aggressive subtypes. The over-arching aim of this research was to identify mechanisms by which miR-200c affects EMT-associated phenotypes, with the long-term aim of utilizing this information to suppress tumorigenesis and metastasis. We hypothesized that miR-200c suppresses a mesenchymal-like phenotype through direct targeting of multiple non-epithelial genes.;Tumorigenesis is a complex process, wherein cancer cells must successfully accomplish multiple steps. For example, cells must lose their apical-basal polarity as they begin to form a primary tumor. In this thesis, I demonstrate that restoring miR-200c to triple negative breast cancer cells restores a more normal structure in 3-D culture. This includes both re-expression, and correct localization of E-cadherin. For metastasis, cells must gain the ability to migrate and invade, as well as the ability to resist anoikis (apoptosis induced upon detachment from the native extracellular matrix). I demonstrate that miR-200c represses the migratory ability of aggressive breast and endometrial cancer cells by directly targeting the extracellular matrix protein fibronectin, and the actin-interacting protein moesin. Lastly, I demonstrate that miR-200c suppresses anoikis resistance in breast cancer cells by directly targeting both components of an autocrine signaling loop, composed of the neurotrophic receptor TrkB and its ligand neurotrophin 3. I made the additional novel observation that these genes are directly up-regulated by NF-kappaB in suspended cells. By identifying how miR-200c exerts its myriad effects, my work has laid the foundation for investigation of new potential therapeutic targets. In particular, resistance to anoikis is a phenotype not currently targeted therapeutically that could prove a potent metastasis suppressor.