Mammary Epithelial Cell Survival Signaling Pathways and the Role of Ubiquitin Modification in Regulating Kinase Activity
My laboratory studies molecular pathways in mammary epithelial cells that initiate inappropriate survival under conditions that would normally induce apoptosis, such as growth factor deprivation, chemotherapy and radiation. We have identified a novel survival pathway in these cells that is initiated through GR activation. Using large-scale gene array analysis, we have further identified several genes that are regulated by GR activation and are implicated in both novel and known survival signaling pathways. We are currently dissecting the individual contributions of the GR-regulated gene products to the survival phenotype. Understanding the mechanism of action of GR-mediated survival is proving to be a useful model for increasing both the understanding of gene regulation by the GR and the identification of novel survival pathways relevant to epithelial cells. These pathways are expected to identify novel targets for inhibitors that can interrupt the development of epithelial cell cancers (by blocking premalignant cell survival) and/or increase sensitivity to cytotoxic agents by increasing apoptosis.