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

Hagai Ligumsky, Ido Wolf, Shira Israeli, Michal Haimsohn, Sarah Ferber, Avraham Karasik, Bella Kaufman, Tami Rubinek*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)449-461
Number of pages13
JournalBreast Cancer Research and Treatment
Issue number2
StatePublished - Apr 2012


FundersFunder number
Riva and Joel Koschitzky Fund for Breast Cancer Research
Sheba Medical Center


    • Breast cancer
    • Exendin-4
    • Glucagon-like peptide-1
    • Type 2 diabetes
    • cAMP


    Dive into the research topics of 'The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells'. Together they form a unique fingerprint.

    Cite this