The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells

Breast Cancer Res Treat. 2012 Apr;132(2):449-61. doi: 10.1007/s10549-011-1585-0. Epub 2011 Jun 3.


The incretin hormone glucagon-like peptide (GLP)-1 is secreted from intestinal L cells in response to food intake, and promotes insulin secretion and pancreatic β-cell proliferation. Reduced GLP-1 levels are observed in obesity and type 2 diabetes mellitus (T2DM) and are associated with reduced insulin secretion and increased insulin resistance. GLP-1 mediates its activities through activation of a G-protein coupled receptor, which is expressed in the pancreas, as well as other tissues. Long-acting GLP-1 receptor (GLP-1R) agonists, such as exendin-4, are currently approved for the treatment of T2DM. As obesity and T2DM are associated with increased risk of breast cancer, we aimed to explore the effects of GLP-1 and exendin-4, on breast cancer cells. Treatment with GLP-1 or exendin-4 reduced viability and enhanced apoptosis of breast cancer cells but did not affect viability of nontumorigenic cells. Moreover, exendin-4 attenuated tumor formation by breast cancer cells in athymic mice. Treatment with either GLP-1 or exendin-4 elevated cAMP levels, activated the down-stream target CREB, and enhanced CRE promoter transcription, in breast cancer cells. Moreover, inhibition of exendin-4-induced adenylate cyclase activation restored cell viability, thus suggesting cAMP as a principle mediator of exendin-4 anti-tumorigenic activity. While the pancreatic form of the GLP-1R could not be detected in breast cancer cells, several lines of evidence indicated the existence of an alternative GLP-1R in mammary cells. Thus, internalization of GLP-1 into MCF-7 cells was evidenced, infection of MCF-7 cells with the pancreatic receptor enhanced proliferation, and treatment with exendin-(9-39), a GLP-1R antagonist, further increased cAMP levels. Our studies indicate the incretin hormone GLP-1 as a potent inducer of cAMP and an inhibitor of breast cancer cell proliferation. Reduced GLP-1 levels may, therefore, serve as a novel link between obesity, diabetes mellitus, and breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclase Inhibitors
  • Adenylyl Cyclases / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Cyclic AMP / metabolism*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Enzyme Activators / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Exenatide
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glucagon-Like Peptide 1 / pharmacology*
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Mice
  • Mice, Nude
  • Peptides / pharmacology*
  • Receptors, Glucagon / agonists
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism
  • Response Elements / drug effects
  • Signal Transduction / drug effects*
  • Time Factors
  • Transcriptional Activation / drug effects
  • Transfection
  • Up-Regulation
  • Venoms / pharmacology*
  • Xenograft Model Antitumor Assays
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Adenylyl Cyclase Inhibitors
  • Antineoplastic Agents
  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Activators
  • Enzyme Inhibitors
  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • Glucagon-Like Peptide 1
  • Exenatide
  • Cyclic AMP
  • p38 Mitogen-Activated Protein Kinases
  • Adenylyl Cyclases