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Environ Toxicol Pharmacol. 2015 Jan;39(1):114-24. doi: 10.1016/j.etap.2014.10.017. Epub 2014 Nov 1.

Collagen density regulates xenobiotic and hypoxic response of mammary epithelial cells.

Author information

1
Department of Cell and Regenerative Biology, University of Wisconsin at Madison, Madison, WI 53706, USA. Electronic address: colleen_curran@hotmail.com.
2
Department of Cell and Regenerative Biology, University of Wisconsin at Madison, Madison, WI 53706, USA. Electronic address: ecarrillo@wisc.edu.
3
Department of Cell and Regenerative Biology, University of Wisconsin at Madison, Madison, WI 53706, USA. Electronic address: ponik@wisc.edu.
4
Department of Cell and Regenerative Biology, University of Wisconsin at Madison, Madison, WI 53706, USA. Electronic address: pjkeely@wisc.edu.

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.

KEYWORDS:

Breast density; Collagen; Focal adhesion kinase (FAK); Hypoxia; Xenobiotics

PMID:
25481308
PMCID:
PMC4323890
DOI:
10.1016/j.etap.2014.10.017
[Indexed for MEDLINE]
Free PMC Article

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