Role of Hepatocyte Growth Factor on Obesity-Mediated Basal-like Breast Cancer (2015)

Undergraduate: Luma Essaid

Faculty Advisor: Liza Makowski
Department: Nutrition

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Recent studies in mice and humans have demonstrated the significance of obesity-induced hepatocyte growth factor (HGF)/c-MET pathway in promoting basal-like breast cancer (BBC), an aggressive triple negative subtype of breast cancer with no targeted therapy. HGF is a protein released from stromal cells, such as fibroblasts, in an inactive form. Once activated, HGF binds to its receptor c-MET, a proto-oncogene, which activates pro-tumor signaling pathways. We have previously demonstrated that obesity increased HGF/c-MET in murine mammary glands and drove early tumor onset in a genetically engineered mouse model of human BBC, C3(1)-TAg mice. To test our hypothesis that weight loss reversed the effects of obesity, mice were weaned onto either a low or high fat diet. We sought to investigate changes in the pro-tumor pathway after a diet switch to induce weight loss prior to tumor onset. Importantly, HGF/c-MET expression in normal mammary glands and c-MET in tumors was elevated with obesity and was significantly reversed with weight loss. We confirmed previous findings that obesity increased expression of HGF from fibroblasts isolated from obese animals compared to lean animals. Interestingly, many of the HGF/c-MET regulators were modified by weight loss after obesity. In summary, weight loss reversed the obesity-mediated pro-tumorigenic pathway. Future research aims to inhibit the HGF/c-MET pathway to evaluate potential treatment for obesity-driven BBC.