The Effects of Obesity on Cellular Stress and mTOR Signaling in Breast Cancer
Introduction. Incidence of obesity has been on the rise since the 1970’s. Obesity is a relative risk for cancer in all populations1. Free fatty acids are known to be increased in obesity blood stream. Free fatty acids can cause many downstream effects in the blood, one is specific in question is its effects on the mTOR pathway2. mTOR pathway integrates a variety of environmental cues to regulate organismal growth and homeostasis normally but increasing free fatty acids cause dysregulation of homeostasis and produce oncogenic effects due to a positive regulation of the pathway3. In this study specific mechanisms that cause fatty acids to affect the mTOR pathway were uncovered. Methods. In vitro breast cancer cell lines where used against siCD36 receptors and control CD36 receptors. Western blotting was also used to determine free fatty acids role on PS6K, a phosphorylated mTOR substrate4. Finally, siRNA was used to determine the role of lysophosphatidic acid acyltransferase-B (LPAAT-B) on the di novo synthesis of phosphatidic acid (PA)5. Results. Results showed that mTOR pathway was increased in obese patients4. Through siCD36 and control, it was concluded that CD36 receptors were needed in order to allow free fatty acids to be up taken into the cell4. Enrichment score showed oleic acid (OA) that are over-represented in association with mTOR signaling4. Research further showed that PA is more positively expressed with LPAAT control versus a siRNA against LPAAT5. Conclusion. One specific way free fatty acid transport into the breast cancer cell is via CD-36 receptor. Once the free fatty acid has been taken into the cell the free fatty acid gives nutrients to allow positive feedforward reaction with the mTOR pathway and allowing an upregulation of the mTOR signaling cascade. The second specific pathway that was determined showed that free fatty acids are converted into fatty acyl Coa which de novo synthesize PA through LPAAT-B. Phosphatidic acid is able to cause an upregulation of mTOR pathway and cause prooncogenic effects to breast cancer cell lines. Thus, further research can be pursued for therapeutic potentials targeting these specific receptors and products to treat distinct breast cancer lineage.
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