Abstract
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.
Highlights
Breast cancer is the leading cause of cancer death among women worldwide [1,2]
Cell proliferation under hyperglycemia In vitro cell proliferation in normal and high glucose was measured by MTS assay in non-tumorigenic breast epithelial cells (MCF10A), estrogen/progesterone-receptor positive breast cancer cells (MCF7), and triple negative breast cancer cells (MDA-231)
Hyperglycemia supports or enhances the growth of non-tumorigenic triple negative breast epithelial cells, which potentially translates to an increased risk of breast cancer in normal tissue or in premalignant lesions
Summary
Breast cancer is the leading cause of cancer death among women worldwide [1,2]. It is well-established that diabetes increases the risk of various cancers including breast, liver, pancreatic, bladder, colorectal, non-Hodgkin’s lymphoma, and endometrial cancer [3]. A great deal of work has shown that cancerous cells become highly dependent on glucose and grow best in media containing highglucose concentrations [7,8]. It is not surprising that diabetes is associated with worse disease progression once cancer is diagnosed [3]
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