Hyperglycemia enhances the proliferation of non-tumorigenic and malignant mammary epithelial cells through increased leptin/IGF1R signaling and activation of AKT/mTOR

PLoS One. 2013 Nov 18;8(11):e79708. doi: 10.1371/journal.pone.0079708. eCollection 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation
  • Fluorescent Antibody Technique
  • Glucose / pharmacology
  • Humans
  • Hyperglycemia / metabolism*
  • Hyperglycemia / pathology*
  • Immunoblotting
  • Leptin / metabolism*
  • MCF-7 Cells
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Leptin
  • MTOR protein, human
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Glucose

Grants and funding

This work was partially supported by HRSA Grant # D34HP16043. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.