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

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 - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.

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.

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Related in: MedlinePlus

Effect of LDIR on tumor phenotypes in genetically diverse F1Bx hosts.(A) Study design for a systems genetics analysis of mammary tumor susceptibility after low dose radiation exposure. (B–D) 10 cGy radiation of mice (B) reduced the incidence of mammary tumors significantly (death without tumors), (C) delayed their time of appearance, and (D) increased tumor growth. The p-values were obtained from Fisher exact test in (B), log rank test in (C), and non-parametric Mann-Whitney U test in (D).
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f1: Effect of LDIR on tumor phenotypes in genetically diverse F1Bx hosts.(A) Study design for a systems genetics analysis of mammary tumor susceptibility after low dose radiation exposure. (B–D) 10 cGy radiation of mice (B) reduced the incidence of mammary tumors significantly (death without tumors), (C) delayed their time of appearance, and (D) increased tumor growth. The p-values were obtained from Fisher exact test in (B), log rank test in (C), and non-parametric Mann-Whitney U test in (D).

Mentions: To examine the effects of LDIR and the stromal microenvironment on mammary tumor development, the endogenous epithelium was surgically removed from F1Bx female mammary glands at 3-weeks of age, and at 11 ~ 12 weeks, mice were either irradiated whole-body with 10 cGy X-rays (LDIR) or sham treated (Figure 1A). Three days post irradiation, un-irradiated inguinal mammary gland fragments from BALB/c Trp53 (p53-/-) mice were transplanted into the LDIR- and sham-treated F1Bx hosts (Figure 1A). Mice were monitored for tumor development by palpation for 18 months. Upon detection, tumor growth rate was determined by measuring tumor volume at each week (see Methods). To measure cytokine levels in plasma, blood was collected from all mice by orbital bleeds at 6 hours and 15 weeks after radiation exposure.


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

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 - Sci Rep (2015)

Effect of LDIR on tumor phenotypes in genetically diverse F1Bx hosts.(A) Study design for a systems genetics analysis of mammary tumor susceptibility after low dose radiation exposure. (B–D) 10 cGy radiation of mice (B) reduced the incidence of mammary tumors significantly (death without tumors), (C) delayed their time of appearance, and (D) increased tumor growth. The p-values were obtained from Fisher exact test in (B), log rank test in (C), and non-parametric Mann-Whitney U test in (D).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352890&req=5

f1: Effect of LDIR on tumor phenotypes in genetically diverse F1Bx hosts.(A) Study design for a systems genetics analysis of mammary tumor susceptibility after low dose radiation exposure. (B–D) 10 cGy radiation of mice (B) reduced the incidence of mammary tumors significantly (death without tumors), (C) delayed their time of appearance, and (D) increased tumor growth. The p-values were obtained from Fisher exact test in (B), log rank test in (C), and non-parametric Mann-Whitney U test in (D).
Mentions: To examine the effects of LDIR and the stromal microenvironment on mammary tumor development, the endogenous epithelium was surgically removed from F1Bx female mammary glands at 3-weeks of age, and at 11 ~ 12 weeks, mice were either irradiated whole-body with 10 cGy X-rays (LDIR) or sham treated (Figure 1A). Three days post irradiation, un-irradiated inguinal mammary gland fragments from BALB/c Trp53 (p53-/-) mice were transplanted into the LDIR- and sham-treated F1Bx hosts (Figure 1A). Mice were monitored for tumor development by palpation for 18 months. Upon detection, tumor growth rate was determined by measuring tumor volume at each week (see Methods). To measure cytokine levels in plasma, blood was collected from all mice by orbital bleeds at 6 hours and 15 weeks after radiation exposure.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.

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.

Show MeSH
Related in: MedlinePlus