Benzo[a]pyrene- and TCDD-induced alterations in tyrosine phosphorylation and insulin-like growth factor signaling pathways in the MCF-10A human mammary epithelial cell line

Previous studies in this laboratory have shown that polycyclic aromatichydrocarbons, such as benzo[a]pyrene (BaP), and certain halogenatedaromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD),modulate receptor signaling pathways in human lymphoid and non- lymphoidcells. We have recently demonstrated that BaP produces a weak mitogenicsignal in human mammary epithelial cells, perhaps by mimicking growthfactor signaling pathways. In the present studies we found that BaP andTCDD activated insulin-like growth factor (IGF-I) signaling pathways underinsulin-deficient conditions. The effects of BaP and TCDD were evaluated inthe human MCF-10A mammary epithelial cell line grown under epidermal growthfactor- and insulin-dependent conditions. BaP (0.3 microM) and TCDD (30 nM)were found to restore a moderate insulin-like signal in MCF-10A cells grownin the absence of added insulin. TCDD was more potent and produced betteractivation of cell growth than did BaP. Both TCDD and BaP appeared to mimicsignaling through the IGF-I receptor (IGF-IR), as evidenced by increasedtyrosine phosphophorylation of IGF-IRbeta, IRS-1 and Shc. In addition, bothBaP and TCDD significantly increased the activity of phosphatidylinositol3- kinase (PI3K). The PI3K inhibitor LY294002 was found to inhibit thegrowth-promoting effects of TCDD seen under insulin-deficient conditions.The results of these studies show that under certain conditions BaP andTCDD can mimic growth factor signaling pathways in human mammary epithelialcells, demonstrating that environmentally prevalent carcinogenic compoundsmay alter cell growth in human mammary epithelial cells via mimicry ofgrowth factor receptor signaling pathways.