The Role of Obesity in Breast Cancer Pathogenesis

Research has shown that obesity increases the risk for type 2 diabetes mellitus (Type 2 DM) by promoting insulin resistance, increases serum estrogen levels by the upregulation of aromatase, and promotes the release of reactive oxygen species (ROS) by macrophages. Increased circulating glucose has been shown to activate mammalian target of rapamycin (mTOR), a significant signaling pathway in breast cancer pathogenesis. Estrogen plays an instrumental role in estrogen-receptor-positive breast cancers. The role of ROS in breast cancer warrants continued investigation, in relation to both pathogenesis and treatment of breast cancer. We aim to review the role of obesity in breast cancer pathogenesis and novel therapies mediating obesity-associated breast cancer development. We explore the association between body mass index (BMI) and breast cancer incidence and the mechanisms by which oxidative stress modulates breast cancer pathogenesis. We discuss the role of glutathione, a ubiquitous antioxidant, in breast cancer therapy. Lastly, we review breast cancer therapies targeting mTOR signaling, leptin signaling, blood sugar reduction, and novel immunotherapy targets

A Novel Regimen for Treating Melanoma: MCL1 Inhibitors and Azacitidine

Although treatment options for melanoma patients have expanded in recent years with the approval of immunotherapy and targeted therapy, there is still an unmet need for new treatment options for patients that are ineligible for, or resistant to these therapies. BH3 mimetics, drugs that mimic the activity of pro-apoptotic BCL2 family proteins, have recently achieved remarkable success in the clinical setting. The combination of BH3 mimetic ABT-199 (venetoclax) plus azacitidine has shown substantial benefit in treating acute myelogenous leukemia. We evaluated the efficacy of various combinations of BH3 mimetic + azacitidine in fourteen human melanoma cell lines from cutaneous, mucosal, acral and uveal subtypes. Using a combination of cell viability assay, BCL2 family knockdown cell lines, live cell imaging, and sphere formation assay, we found that combining inhibition of MCL1, an anti-apoptotic BCL2 protein, with azacitidine had substantial pro-apoptotic effects in multiple melanoma cell lines. Specifically, this combination reduced cell viability, proliferation, sphere formation, and induced apoptosis. In addition, this combination is highly effective at reducing cell viability in rare mucosal and uveal subtypes. Overall, our data suggest this combination as a promising therapeutic option for some patients with melanoma and should be further explored in clinical trials