The Role of Hepatocyte Growth Factor in Obesity-induced Basal-like Breast Cancer
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Essaid, Luma. The Role of Hepatocyte Growth Factor In Obesity-induced Basal-like Breast Cancer. 2015. https://doi.org/10.17615/f833-6308APA
Essaid, L. (2015). The Role of Hepatocyte Growth Factor in Obesity-induced Basal-like Breast Cancer. https://doi.org/10.17615/f833-6308Chicago
Essaid, Luma. 2015. The Role of Hepatocyte Growth Factor In Obesity-Induced Basal-Like Breast Cancer. https://doi.org/10.17615/f833-6308- Last Modified
- February 26, 2019
- Creator
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Essaid, Luma
- Affiliation: Gillings School of Global Public Health, Department of Nutrition
- Abstract
- Obesity is a well-known modifiable risk factor for many diseases, including cancer. Recent studies in mice and humans have demonstrated the significance of the microenvironment in shaping cancer risk and progression. This study investigated the obesity-induced hepatocyte growth factor (HGF)/cMET signaling pathway in promoting basal-like breast cancer (BBC), an aggressive triple negative subtype of breast cancer with no targeted therapy. HGF is a secreted protein released from stromal cells in an inactive form. Once activated, HGF binds to its receptor cMET, a proto-oncogene, which activates pro-tumor signaling pathways. We have previously demonstrated that obesity increases HGF/cMET in murine mammary glands and drives early tumor onset in a genetically engineered mouse model (GEMM) of human BBC, C3(1)-Tag mice. To test our hypothesis that weight loss would reverse the effects of obesity, mice were weaned at 3 weeks of age onto either a low fat (10% kcal from fat) or high fat (60% kcal from fat) diet. We sought to investigate changes in the pro-tumor pathway after a diet switch at 10 weeks of age, from 60% kcal from fat to 10%, by inducing weight loss prior to tumor onset. Importantly, HGF/cMET expression in normal mammary glands, and cMET in tumors, was elevated with obesity and was significantly reversed with weight loss. This study also quantified adipocyte area in normal mammary and tumor tissue between the 10% kcal from fat and 60% kcal from fat diets to study diet effects on adipocyte size. Interestingly, many of the HGF/cMET regulators, e.g., activators such as HGF-Activator, and inhibitors such as HGF-Activator Inhibitor were modified in the weight-loss mice between Normal Associated Fibroblasts and Cancer Associated Fibroblasts. Finally, we confirmed that C3(1)-Tag mammary tumor epithelial cells grown in conditioned media from fibroblasts of differing diets, 10% and 60% kcal from fat, have distinctive proliferation indices. In summary, these results indicate that low and high fat diets have differential effects on murine phenotypes, including body weight, body composition, and stromal microenvironment. Importantly, weight loss in adulthood is possible, which reversed the obesity-mediated pro-tumorigenic pathway. Future research aims include implementing weight loss as a preventative measure in human subjects and inhibiting the HGF/cMET pathway to evaluate potential treatment for obesity-driven BBC.
- Date of publication
- spring 2015
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- DOI
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- In Copyright
- Note
- Funding: Gold Summer Undergraduate Research Fellowship, Tom and Elizabeth Long Research Award for Honors Research
- Advisor
- Makowski, Liza
- Degree
- Bachelor of Science in Public Health
- Honors level
- Highest Honors
- Degree granting institution
- University of North Carolina at Chapel Hill
- Extent
- 33
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