MicroRNA-200c: A Novel Way to Attack Breast Cancer Metastases by Restoring the Epithelial Phenotype
Annual rept. 19 Jan 2011-18 Jan 2012
COLORADO UNIV AURORA CO
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Background Epithelial to mesenchymal transition EMT is a well-established process during embryonic development and cancer progression. Our studies show that a particular microRNA, miR-200c maintains epithelial cell identity. Hypothesis We hypothesize that reintroduction of miR-200c to aggressive breast cancer cells in vivo will restore the epithelial phenotype and thereby render them less aggressive. Results We have identified novel mechanisms by which miR-200c represses neuronal and mesenchymal genes that should not be expressed in epithelial cells. Such genes are inappropriately allowed to be translated in TNBC lines that have lost miR-200c. We have identified targets of miR-200c that mediate cell migration. We show that these are direct targets and that when miR-200c is restored to TNBC cells, migration is decreased because miR-200c targets the genes encoding fibronectin and moesin. We find that restoration of miR- 200c to TNBC cells renders there morphology in 3D culture smaller and rounder as opposed to their usual stellate, invasive structures. We also demonstrate that miR-200c can reverse anoikis resistance in TNBC and we identified TrkB and its ligand NTF3as the direct target that mediates this effect. We find that restoration of miR-200c represses the ability to migrate and invade, and to resist anoikis and chemotherapy, all important steps in the metastatic cascade. Thus, restoration of miR-200c has exciting potential therapeutic value, but further in vivo studies are necessary as proof of principal for feasibility and practicality of non-viral mediated delivery.
- Medicine and Medical Research