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 aromatic hydrocarbons, such as benzo[a]pyrene (BaP), and certain halogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), modulate receptor signaling pathways in human lymphoid and non-lymphoid cells. We have recently demonstrated that BaP produces a weak mitogenic signal in human mammary epithelial cells, perhaps by mimicking growth factor signaling pathways. In the present studies we found that BaP and TCDD activated insulin-like growth factor (IGF-I) signaling pathways under insulin-deficient conditions. The effects of BaP and TCDD were evaluated in the human MCF-10A mammary epithelial cell line grown under epidermal growth factor- 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 grown in the absence of added insulin. TCDD was more potent and produced better activation of cell growth than did BaP. Both TCDD and BaP appeared to mimic signaling through the IGF-I receptor (IGF-IR), as evidenced by increased tyrosine phosphophorylation of IGF-IRbeta, IRS-1 and Shc. In addition, both BaP and TCDD significantly increased the activity of phosphatidylinositol 3-kinase (PI3K). The PI3K inhibitor LY294002 was found to inhibit the growth-promoting effects of TCDD seen under insulin-deficient conditions. The results of these studies show that under certain conditions BaP and TCDD can mimic growth factor signaling pathways in human mammary epithelial cells, demonstrating that environmentally prevalent carcinogenic compounds may alter cell growth in human mammary epithelial cells via mimicry of growth factor receptor signaling pathways.
Toxicology Program, University of New Mexico College of Pharmacy, Albuquerque 87131, USA.
S L
SL
Tannheimer
S P
SP
Ethier
K K
KK
Caldwell
S W
SW
Burchiel
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D002273:Carcinogens / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000172:deficiency; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002273:Carcinogens; D003470:Culture Media; D007328:Insulin; D000072317:Polychlorinated Dibenzodioxins; D011506:Proteins; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D001564:Benzo(a)pyrene; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1