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

Scientific Reports
Pengju ZhangJian-Hua Mao

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...Continue Reading

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Citations

Dec 15, 2015·Breast Cancer Research and Treatment·William C HinesMina J Bissell
Mar 26, 2016·Frontiers in Oncology·Mary Helen Barcellos-Hoff, Jian-Hua Mao
Aug 11, 2015·Life Sciences in Space Research·Mary Helen Barcellos-HoffMichael M Weil
Jul 16, 2016·The British Journal of Radiology·Richard P Hill
Jun 6, 2018·Frontiers in Cell and Developmental Biology·James B McCarthyEva A Turley
Apr 22, 2017·Science·Claire Robertson

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Methods Mentioned

BETA
X-ray
genotyping
lavage
enzyme-linked immunosorbent assay

Software Mentioned

SPSS
Ingenuity Pathway Analysis ( IPA )
ImageJ

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