Aryl Hydrocarbon Receptor Ligands Inhibit IGF-II and Adipokine Stimulated Breast Cancer Cell Proliferation

Abstract

Obesity increases human cancer risk and the risk for cancer recurrence. Adipocytes secrete paracrine factors termed adipokines that stimulate signaling in cancer cells that induce proliferation. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that plays roles in tumorigenesis, is regulated by exogenous lipophilic chemicals, and has been explored as a therapeutic target for cancer therapy. Whether exogenous AHR ligands modulate adipokine stimulated breast cancer cell proliferation has not been investigated. We provide evidence that adipocytes secrete insulin-like growth factor 2 (IGF-2) at levels that stimulate the proliferation of human estrogen receptor (ER) positive breast cancer cells. Using highly specific AHR ligands and AHR short interfering RNA (AHR-siRNA), we show that specific ligand-activated AHR inhibits adipocyte secretome and IGF-2-stimulated breast cancer cell proliferation. We also report that a highly specific AHR agonist significantly (P < 0.05) inhibits the expression of E2F1, CCND1 (known as Cyclin D1), MYB, SRC, JAK2, and JUND in breast cancer cells. Collectively, these data suggest that drugs that target the AHR may be useful for treating cancer in human obesity.