ToxSci Advance Access originally published online on August 5, 2004
Toxicological Sciences 2004 82(1):46-61; doi:10.1093/toxsci/kfh242
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Toxicological Sciences vol. 82 no. 1 © Society of Toxicology 2004; all rights reserved.
Linked Expression of Ah Receptor, ARNT, CYP1A1, and CYP1B1 in Rat Mammary Epithelia, in Vitro, Is Each Substantially Elevated by Specific Extracellular Matrix Interactions that Precede Branching Morphogenesis
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* Department of Pharmacology and the Environmental Toxicology Center, University of Wisconsin Medical School, Madison, Wisconsin 53706, and Department of Biology, University of South Florida, Tampa, Florida 33620
Received June 3, 2004; accepted July 28, 2004
Cytochrome P4501B1 (CYP1B1), the major constitutively expressed CYP in the rat mammary gland, is induced by Ah-receptor (AhR) ligands, while CYP1A1 is predominately expressed only after induction. These CYPs contribute to carcinogenic activation of polycyclic aromatic hydrocarbons (PAHs). AhR, ARNT, and CYP1B1 were only weakly expressed, even after 2,3,7,8-tetrachlorodibenzo-p-dioxin induction, when rat mammary epithelial cells (RMEC) were cultured on plastic. RMEC cultured on the extracellular matrix (ECM), Matrigel, or on a floating gel of collagen I demonstrated branching morphogenesis and substantially increased basal CYP1B1 and induced CYP1A1 expression, in parallel with large increases in AhR and ARNT expression. Branching was more pronounced in the Wistar Kyoto than in the Wistar Furth rat strain. Although EGF enhanced branching, neither strain nor growth factor treatment substantially impacted CYP expression. Increased AhR and ARNT expression is observed within 24 h of dispersal on Matrigel, substantially prior to branch formation. Culture on thin layers of collagen I, collagen IV, and laminin, respectively, failed to reproduce the branching morphogenesis or increases in AhR, ARNT, or CYP expression. However, adherent, gelled collagen I recapitulated the increased protein expression, without supporting branching. This increased protein expression was closely paralleled by enhanced expression of ß-catenin and E-cadherin, components of cell-cell adhesion complexes. A synthetic peptide that selectively antagonizes integrin-ECM interactions reduced branch formation, without diminishing AhR, ARNT, and CYP expression. These data demonstrate that early ECM surface adhesion interactions mediate AhR and ARNT expression, which enhances CYP expression, independent of branching morphogenesis.
Key Words: CYP1B1; CYP1A1; AhR; ARNT; ECM; branching morphogenesis.
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