The novel hypothesis to be examined in this proposal is that Beclin 1 plays an autophagy-independent role in breast cancer through the regulation of endocytic trafficking and the promotion of IGF-1R signaling. Beclin 1 expression is frequently decreased in human tumors, including breast cancer, and decreased expression in mice promotes tumorigenesis, establishing Beclin 1 as a haploinsufficient tumor suppressor gene. Although much research has focused on the role of Beclin 1 in autophagy as the mechanism by which it exerts its tumor suppressor action, alternative functions of Beclin 1 that could contribut to its role in cancer have received less attention. This is significant because Beclin 1 is an essential component of the core complex that regulates not only autophagy, but also endocytic trafficking, which can impact growth factor receptor signaling. In this regard, the applicant made the novel discovery that loss of Beclin 1 enhances IGF-1R activation and downstream signaling to AKT in breast carcinoma cells and that these changes in signaling are associated with increased growth and invasion. The significance of the IGF-1R signaling pathway for breast cancer is underscored by the fact that expression of phosphorylated IGF-1R is a prognostic indicator of reduced patient survival. The clinical importance of the IGF-1R and the need to develop improved approaches for identifying patients to be treated with IGF-1R-targeted therapies highlight the importance of investigating further the novel Beclin 1-mediated mechanism for regulating IGF-1R signaling that the applicant has identified and deciphering its contribution to breast cancer. Preliminary data support an autophagy-independent mechanism for the involvement of Beclin 1 in the regulation of IGF-1R signaling and point toward a mechanism involving the control of endocytic trafficking of the receptor. Further investigation is warranted to understand how the spatial and temporal control of receptor signaling by this essential membrane trafficking pathway contributes to tumor progression. To investigate the hypothesis that Beclin 1 controls breast cancer progression through the autophagy- independent regulation of IGF-1R endocytic trafficking, the applicant will: 1) Establish the role o Beclin 1 in the regulation IGF-1R signaling. The hypothesis that loss of Beclin 1 sustains IGF-1R/IRS-2 signaling by preventing early endosome maturation and subsequent downregulation of the activated receptor by lysosomal degradation will be examined;2) Investigate the hypothesis that Beclin 1 suppresses breast carcinoma progression through its control of IGF-1R signaling. The hypothesis that sustained activation of the IGF-1R upon loss of Beclin 1 expression enhances survival, invasion and metastasis of breast carcinomas will be examined. The correlation between Beclin 1 expression and IGF-1R/IRS-2/AKT signaling in the pre-malignant mammary gland and human breast tumors will also be assessed.
Novel approaches are needed to identify tumors that will be responsive to a specific targeted therapy so that a more personalized approach to the selection of patients who would gain benefit from treatment can be developed. In this proposal, one mechanism by which tumors are made more sensitive to targeted therapy will be examined. The longterm goal of this project is to use the information gained for biomarker development or the development of potential combination therapies to treat breast cancer patients. !