Molecular determinants of breast cancer malignancy

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DESCRIPTION (provided by applicant): The oncoprotein, osteopontin (OPN) expressed by tumor cells potentiates their malignant properties, specifically by affecting their ability to grow, invade, and metastasize. Our research shows that OPN downregulates the protein levels of the tumor suppressor protein, Merlin, likely by targeting it for degradation in breast cancer cells. Merlin is a tumor suppressor gene that has been well characterized in various tumor types of the nervous system. In nervous system tumors, Merlin mediates contact inhibition, invasion, cell growth and also impedes proliferation. Recent evidence also implicates that Merlin protein gets degraded rapidly in the above tumor types following post-translation modifications, including Akt-mediated phosphorylation followed by ubiquitination. Merlin is understudied in breast cancer. Interestingly, we also discovered that Merlin exerts a negative regulatory effect on OPN. Based on these findings, we hypothesize that Merlin and OPN reciprocally regulate each other. A balance between the levels of the two proteins is critical to the maintenance of non-malignant cell behavior. Merlin keeps OPN levels under check in untransformed cells. During the pathogenesis of breast cancer OPN levels are known to increase (as a result of multiple aberrant signaling pathways). We propose that following signaling via OPN, activated phospho-Akt phosphorylates Merlin. Phosphorylated Merlin is targeted for proteasomal degradation. Thus, with the advancement of breast cancer, the increase in OPN decreases stability of Merlin, resulting in an overall decreased pool of Merlin in the cells. This disrupts the normal physiological balance between Merlin and OPN. This vicious cycle promotes malignant progression of breast cancer. Our overall objectives are (i) to elucidate the significance of Merlin in breast cancer and, (ii) to understand the mechanism of reciprocal regulation of Merlin and OPN in breast cancer. Towards this, we have proposed the following Specific Aims. Specific Aim 1: Test the hypothesis that by modulating Merlin levels we can regulate the malignant behavior of breast cancer cells. Specific Aim 2: Understand the mechanism of reciprocal regulation of Merlin and OPN in breast cancer. Specific Aim 3: Determine the correlation between expression of OPN and Merlin in patient-derived breast cancer specimens. Expected outcome & Impact: The proposed studies will lead to a better understanding of the role of Merlin in breast cancer progression & will reveal a yin-and-yang relationship between the OPN and Merlin. The ability to potentially use Akt/PI-3-kinase and proteasome inhibitors to stabilize Merlin protein is a treatment modality that can be explored in patients to reinstate the growth-inhibitory activity of Merlin. PUBLIC HEALTH RELEVANCE: The proposed studies will lead to a better understanding of the role of the tumor suppressor, Merlin, in breast cancer progression. Our research will reveal a yin-and-yang relationship between the oncoprotein, OPN and the tumor suppressor, Merlin. Our studies will lay the foundation for considering the use of Akt/PI-3-kinase and proteasome inhibitors to stabilize Merlin protein as treatment options for breast cancers that have lost the expression of Merlin concomitant with a gain in OPN expression.