Hyperglycemia Enhances the Proliferation of Non-Tumorigenic and Malignant Mammary Epithelial Cells through Increased leptin/IGF1R Signaling and Activation of AKT/mTOR

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.

Expression characteristics of proteins of IGF-1R, p-Akt, and survivin in papillary thyroid carcinoma patients with type 2 diabetes mellitus

“…[18–20] In addition, hyperglycemia characterized with diabetes directly or indirectly promotes IGF-1R phosphorylation (activation) by stimulating advanced glycation end product production to facilitate tumor cell proliferation. [21,22] Our results indicated that IGF-1R may mediate the mechanism of PTC carcinogenesis in diabetes.…”

Role of tumor microenvironment in tumorigenesis

“…Leptin, an adipocyte-derived cytokine, would arouse proliferation in some cell types, such as mammary epithelium, which has an effect on the neoplasm cell proliferation, apoptosis, and cell cycle 205-207. Data has shown that high glucose levels can induce leptin signaling directly 208. Additionally, adiponectin in given cells may inhibit proliferation promoting apoptosis through the adenosine monophosphate kinase (AMPK) and MAPK pathways 180.…”

The biochemical alterations underlying post-burn hypermetabolism

“…Initially, elevated levels of glucose serve as an efficient energy source and have been reported to increase cell proliferation, foster wound healing and mediate a switch from oxidative phosphorylation to glycolysis [139], [140] and [141]. However, these effects appear to be tissue specific, with much of the literature suggesting apoptotic effects with increasing levels of glucose [142] and [143].…”