Obesity and diabetes are associated with increased breast cancer risk and worse disease progression once cancer is diagnosed; however, the exact etiology behind these observations remains to be fully elucidated. Due to the global obesity/diabetes pandemic, it is imperative to understand how these diseases promote and enhance breast cancer and other common cancers. In this study we demonstrate that hyperglycemia promotes breast cancer by altering leptin/IGF1R and AKT/mTOR signaling. To our knowledge, we show for the first time that in breast epithelial cells, hyperglycemia alone directly impacts leptin signaling. Hyperglycemia increased proliferation of both non-tumorigenic and malignant mammary epithelial cells. These observations coincided with increased leptin receptor and IGF1R receptor, as well as, increased levels of GRB2, pJAK2, pSTAT3, pIRS1/2, pAKT, and p-mTOR. Moreover, pJAK2 was almost completely colocalized with leptin receptor under high glucose conditions. These results demonstrate how hyperglycemia can potentially increase the risk of breast cancer in premalignant lesions and enhance cancer progression in malignant cells.

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Introduction: It is now well-appreciated that diabetes and obesity increase the risk of breast cancer in women and result in worse disease progression once breast cancer is diagnosed. Moreover, breast cancer rates are increasing worldwide and breast cancer is now the most common malignancy in women across the globe. However, the exact etiology behind increased breast cancer incidence and severity observed in overweight/diabetic patients remains to be fully elucidated. Many experts now concede that diabetes/obesity have reached epidemic proportions globally. Therefore, it is particularly important to understand how these two chronic diseases promote and enhance the development of breast cancer, as well as, other common forms of cancer. Methods: A normal breast epithelial cell line (MCF10A) and two malignant breast epithelial cell lines (MCF7, MB-MDA-231) were treated with three different glucose concentrations: normal (5.5mM), prediabetic (10mM), and diabetic (25mM). The effects of increasing glucose on cell proliferation and intracellular signaling were assessed at 24hr, 48hr, and 72hr. MTS assay was used to monitor cell proliferation and Annexin V/propidium iodide staining was used to monitor apoptosis/cell death. Intracellular signaling intermediates were assessed via Western blot. Results: Prediabetic and diabetic glucose enhanced proliferation of both normal and malignant breast cells. Normal cells exhibited the greatest increase in cell growth. No major changes in apoptosis or cell death were observed for either normal or malignant cells. The three most abundant leptin receptor isoforms were significantly upregulated with increasing glucose in both normal and malignant cells. Likewise, GRB2, PTP1B, and SOCS3 were significantly upregulated with increasing glucose. Transient increases in JAK2 phosphorylation also occurred in all three cell lines with increasing glucose. In contrast, STAT3 phosphorylation was not significantly altered in malignant cells but was transiently increased in normal cells with increasing glucose. Transient but significant increases in mTOR phosphorylation were also observed for all three cell lines with increasing glucose and this generally corresponded with transient suppression of AMPK phosphorylation. Conclusions: To our knowledge, we demonstrate for the first time that in the absence of hyperleptinemia or hyperinsulinemia increasing glucose levels can, by themselves, directly impact leptin-receptor signaling in breast epithelial cells. Our results implicate leptin-receptor signaling in the pathogenesis of hyperglycemia in both normal and malignant cells. Components of this pathway may be useful targets for the prevention and treatment of diabetes, obesity, and ultimately breast cancer. Citation Format: Rebecca Lopez, Pamela Agullo, Arunkumar Arumugam, Riya Joseph, Kanika Monga, Sushmita Nandy, Thiyagarajan Boopalan, Christina Gutierrez, Jacqueline Parada, Rajkumar Lakshmanaswamy. Prediabetic and diabetic levels of glucose enhance the proliferation of normal and malignant breast epithelial cells via increased leptin signaling and activation of mTOR. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1862. doi:10.1158/1538-7445.AM2013-1862