title: Collagen density regulates xenobiotic and hypoxic response of mammary epithelial cells.
abstract: Breast density, where collagen I is the dominant component, is a significant breast cancer risk factor. Cell surface integrins interact with collagen, activate focal adhesion kinase (FAK), and downstream cell signals associated with xenobiotics (AhR, ARNT) and hypoxia (HIF-1α, ARNT). We examined if mammary cells cultured in high density (HD) or low density (LD) collagen gels affected xenobiotic or hypoxic responses. ARNT production was significantly reduced by HD culture and in response to a FAK inhibitor. Consistent with a decrease in ARNT, AhR and HIF-1α reporter activation and VEGF production was lower in HD compared to LD. However, P450 production was enhanced in HD and induced by AhR and HIF-1α agonists, possibly in response to increased NF-κB activaton. Thus, collagen density differentially regulates downstream cell signals of AhR and HIF-1α by modulating the activity of FAK, the release of NF-κB transcriptional factors, and the levels of ARNT.
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin at Madison, Madison, WI 53706, USA. Electronic address: colleen_curran@hotmail.com.
authors.forename: Colleen S
authors.initials: CS
authors.lastname: Curran
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin at Madison, Madison, WI 53706, USA. Electronic address: ecarrillo@wisc.edu.
authors.forename: Esteban R
authors.initials: ER
authors.lastname: Carrillo
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin at Madison, Madison, WI 53706, USA. Electronic address: ponik@wisc.edu.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Ponik
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin at Madison, Madison, WI 53706, USA. Electronic address: pjkeely@wisc.edu.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keely
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D001940:Breast / Q000166:cytology*; D002460:Cell Line; D003094:Collagen / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: C497396:ARNT protein, human; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D015262:Xenobiotics; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D000072000:NF-KappaB Inhibitor alpha; D003094:Collagen; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
keywords: Breast density; Collagen; Focal adhesion kinase (FAK); Hypoxia; Xenobiotics