When normal differentiated epithelial cells are exposed to various stresses, they typically activate a proliferative arrest. This arrest prevents the fixation of mutations within damaged DNA and prevents the expansion of a mutated variant population of cells. Interestingly, as explained in the Overview, there is a rare population of cells that does not initiate proliferative arrest when exposed to stress signals. Stem cells instead are recruited to the site of stress, migrate towards the signals and participate in wound healing and restoration of the damaged tissue by proliferating and differentiating. This process under normal circumstances is self-limiting and the cellular programs that underlie motility, repackaging of chromatin and altered signaling are inactivated. However, if these cells acquire oncogenic mutations, they now fail to shut down the wounding response and continue inappropriate proliferation, movement and behaviors. We have developed a model system where specific oncogenic mutations provide the cell with a repertoire of responses that are seen in advanced malignancy, the activation of an epithelial-to-mesenchymal transition (EIVIT). This Project will (1) determine the program of acquired events that accompany the activation of EMT in pre-cancerous epithelial cells (structural changes in DNA, DNA methylation events, expression changes and microRNA changes. We will (2) determine the program of acquired events that accompany the activation of EMT in pre-cancerous epithelial cells when co-cultured with normal breast fibroblasts and carcinoma-associated breast fibroblasts (structural changes in DNA, DNA methylation events, expression changes and microRNA changes. We will also (3) modulate specific pathways that participate in the transmission of mechanical forces that transmit information within the cell. Finally, we will (4) use our insights to develop markers and identify therapeutic targets which will aid in using this information in a clinically relevant fashion.
We are learning that signals from preneoplastic cells can interact with stromal components to facilitate accelerated evolution and generate drug-resistant and metastatic cells. We hope to understand these processes and use what we are learning from the stromal environment to compose artificial selection pressures that will guide the genetically diverse cells into harmless endpoints.
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