The Role of Leptin and Leptin-Mediated Pathways on the Epithelial-Mesenchymal Transition in Breast Cancer of Obese Individuals
Introduction. Breast cancer continues to be a leading cause of mortality for women worldwide, while obesity remains a leading cause of morbidity within the United States and serves as a risk factor for the development and progression of breast cancer1-4. However, the mechanisms that underlie the connection between obesity and breast cancer, specifically triple-negative breast cancer (TNBC), are incompletely understood5. An important marker for metastasis in breast cancer progression is the epithelial-mesenchymal transition (EMT)6. Associated with the procancer effects of obesity is an increase in levels of circulating leptin5. As a result, leptin and leptin-mediated pathways, such as the JAK2-STAT3 pathway, serve as areas of exploration in slowing the EMT transition process in breast cancer. Methods. To assess for EMT progression factors, three TNBC cell groups, including two murine groups and one human group, are used and supplemented with either a diet-induced obesity (DIO) serum or control serum5. An association is made between EMT-related genes and leptin signaling through incorporation of two new cell groups, one control and one with a knockdown of the leptin receptor, and then mRNA levels are measured5. Additionally, EMT cell markers, such as E-cadherin and vimentin, are analyzed through the usage of two mouse models, one control mouse and one study mouse, ThrbPv/PvPten+/-, when mice are given a low-fat diet or high-fat diet as well as when administered a STAT3 inhibitor, S3I-2017. Results. In all three TNBC cell lines, administration of the DIO serum results in both an increase in cell viability and the number of invading cells when compared with the control serum5. The EMT genes that have diminished expression levels from the knockdown of the leptin receptor include: Foxc2, Twist2, and Vim5. With administration of a high fat diet, there is an increase in expression of vimentin protein levels and a decrease in E-cadherin protein levels when compared with the low fat diet7. The opposite is seen with administration of S3I-201, as E-cadherin protein levels increase while vimentin protein levels decrease7. Conclusions. Leptin signaling is causally linked to obesity-associated breast cancer development. Foxc2, Twist2, and Vim are upregulated by leptin and play an important role in the progression of EMT. The use of S3I-201 reduces EMT signals, invasiveness and migration, and future clinical trials are necessary to assess its effectiveness in humans.
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