Autophagy and TGF-Beta Antagonist Signaling in Breast Cancer at Premetastatic Sites
Technical Report,01 May 2013,31 Mar 2015
Sloan-Kettering Institute for Cancer Research New York United States
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The majority of breast cancer mortality is caused by metastatic relapse, which requires the reactivation and outgrowth of tumor cells after they have disseminated to pre-metastatic sites and undergone prolonged dormancy. Understanding the mechanisms underpinning dormancy, reactivation, and outgrowth will provide novel approaches for the prevention and treatment of metastatic diseases. We discovered the TGF signaling antagonist Coco as a mediator of the reactivation of lung-disseminated breast cancer cells. We also made contributions to the mechanistic understanding and cancer relevance of autophagy, a catabolic response sustaining cancer cell survival under stress and therapeutic treatment. In this proposal, we investigate the role of autophagy and its interplay with Coco signaling in breast cancer dormancy and metastatic relapse, and the therapeutic potential of targeting autophagy for the treatment of breast cancer metastasis. Over the period supported by this grant, we have further deepened our understanding of the Coco signaling in dormancy reactivation, and the mechanisms and tumorigenic role of autophagy. We have developed a series of genetically controlled cancer cell models for in vivo mouse studies to define the roles and interplay of Coco signaling with autophagy in breast cancer dormancy and reactivation. Monoclonal antibodies against Coco have also been developed for future Coco-targeted therapies. Experiments utilizing mouse models to determine the in vivo effect of autophagy on breast cancer dormancy at lung premetastatic sites are ongoing.