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Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment.

Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment.

Authors :
Zhang P
Lo A
Huang Y
Huang G
Liang G
Mott J
Karpen GH
Blakely EA
Bissell MJ
Barcellos-Hoff MH
Snijders AM
Mao JH
Source :
Scientific reports [Sci Rep] 2015 Mar 09; Vol. 5, pp. 8919. Date of Electronic Publication: 2015 Mar 09.
Publication Year :
2015

Abstract

The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGFβ1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGFβ1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures.

Details

Language :
English
ISSN :
2045-2322
Volume :
5
Database :
MEDLINE
Journal :
Scientific reports
Publication Type :
Academic Journal
Accession number :
25747469
Full Text :
https://doi.org/10.1038/srep08919