Mechanisms of metformin-induced c-MET downregulation in triple-negative breast cancer

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PROJECT SUMMARY Over 250,000 new cases of invasive breast cancer are expected to be diagnosed in the United States each year. Triple-negative breast cancer is a breast cancer subtype that accounts for 20% of all breast cancers diagnosed. Approximately 50,000 new cases of triple-negative breast cancer are diagnosed each year. Triple- negative breast cancer is also noted as a health disparity, being that it is most common in African-American women. Unfortunately, triple-negative breast cancer is associated with poor prognosis, often spreading to other tissues resulting in a mortality rate. This type of breast cancer is very difficult to treat because it lacks common markers targeted by cancer drugs. Therefore, scientists are developing new drugs to target molecular markers found in triple-negative breast cancers. With this, led to the testing of metformin, a drug already widely used to treat diabetes, for the treatment of triple-negative breast cancer. Interestingly, scientists discovered that fewer diabetes patients taking metformin developed cancer over time. Although metformin is safe for patients to take, the mechanism by which metformin kills cancer cells is not fully understood. The objective of this study is to investigate the mechanism of metformin-mediated c-MET regulation in its killing of basal like breast cancer (BLBC)/TNBC cells. Based on previous studies and our preliminary data, we hypothesize that downregulation of c-MET and the associated inhibition of cell proliferation and CSC self-renewal is a critical determinant of metformin-mediated inhibition of basal-like/TNBC cells. The specific aims are: 1) To determine the effects of metformin-induced c-MET inhibition on TNBC cell growth and stemness; 2) To determine the molecular mechanism of metformin-induced c-MET downregulation; and 3) To determine the impact of metformin- induced c-MET downregulation on Wnt signaling in cancer stem cell stemness inhibition. At the end of this project, we hope to have an understanding of how metformin kills triple-negative breast cancer cells and how this can be translated to future animal and human studies. In addition to research project accomplishment, I will also gain specific training in professional communication, grant writing, community outreach, and studies on cancer health disparity issues. Ultimately, the knowledge gained from our work will contribute to the elimination of cancer-related challenges associated with triple-negative breast and may be applied to other cancers to reduce the overall cancer burden.