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 ( ) 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. 1. Introduction Human obesity is common and has been linked with increases in breast cancer risk and breast cancer recurrence [1–3]. Although the underlying links between obesity and cancer are not completely clear, adipocytes themselves are postulated to play a role [1–9]. Adipocytes secrete multiple paracrine factors termed adipokines that stimulate signaling in human cancer cells that stimulate proliferation [4–7, 9]. Specific adipokines that stimulate the proliferation of human estrogen receptor (ER) positive breast cancer cells are leptin, collagen VI, and members of the insulin-like growth factor (IGF) family of proteins [4–6, 8, 9]. In ER positive breast cancer cells, leptin through its cognate membrane spanning cytokine leptin receptor activates the JAK/STAT pathway [6, 10]. Collagen VI by activating the NG2/chondroitin sulfate proteoglycan receptor activates AKT and β-catenin signaling [4, 5]. IGF-1 and IGF-2 signal through specific cell surface tyrosine kinase receptors, IGF-1 receptor (IGF-1R) and insulin receptor isoform A (IR-A)), that are highly expressed on human ER expressing breast cancer cells [11, 12]. The critical pathway by which IGF-1 and IGF-2 stimulate breast cancer cell proliferation is the PI3K pathway that leads to increases in AKT activity [11, 12]. Leptin, collagen VI, and IGF proteins have all been reported to stimulate
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