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

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.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [1];  [1]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  2. NYU School of Medicine, New York, NY (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1190780
Alternate Identifier(s):
OSTI ID: 1407333
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 5; Journal Issue: 5; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; cancer genetics; cancer microenvironment

Citation Formats

Zhang, Pengju, Lo, Alvin, Huang, Yurong, Huang, Ge, Liang, Guozhou, Mott, Joni, Karpen, Gary H., Blakely, Eleanor A., Bissell, Mina J., Barcellos-Hoff, Mary Helen, Snijders, Antoine M., and Mao, Jian-Hua. Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment. United States: N. p., 2015. Web. doi:10.1038/srep08919.
Zhang, Pengju, Lo, Alvin, Huang, Yurong, Huang, Ge, Liang, Guozhou, Mott, Joni, Karpen, Gary H., Blakely, Eleanor A., Bissell, Mina J., Barcellos-Hoff, Mary Helen, Snijders, Antoine M., & Mao, Jian-Hua. Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment. United States. doi:10.1038/srep08919.
Zhang, Pengju, Lo, Alvin, Huang, Yurong, Huang, Ge, Liang, Guozhou, Mott, Joni, Karpen, Gary H., Blakely, Eleanor A., Bissell, Mina J., Barcellos-Hoff, Mary Helen, Snijders, Antoine M., and Mao, Jian-Hua. Mon . "Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment". United States. doi:10.1038/srep08919. https://www.osti.gov/servlets/purl/1190780.
@article{osti_1190780,
title = {Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment},
author = {Zhang, Pengju and Lo, Alvin and Huang, Yurong and Huang, Ge and Liang, Guozhou and Mott, Joni and Karpen, Gary H. and Blakely, Eleanor A. and Bissell, Mina J. and Barcellos-Hoff, Mary Helen and Snijders, Antoine M. and Mao, Jian-Hua},
abstractNote = {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.},
doi = {10.1038/srep08919},
journal = {Scientific Reports},
number = 5,
volume = 5,
place = {United States},
year = {2015},
month = {3}
}

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