Limits...
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.

Show MeSH

Related in: MedlinePlus

Effect of host genetic background on mammary gland architecture.(A) Whole-mount imaging mammary gland by optical microscopy. Mammary glands were collected at 10 weeks after birth from BALB/c, SPRET/EiJ, and F1 hybrids between BALB/c and SPRET/EiJ. (B) Quantification of mammary gland branching. The p-values were obtained by t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4352890&req=5

f4: Effect of host genetic background on mammary gland architecture.(A) Whole-mount imaging mammary gland by optical microscopy. Mammary glands were collected at 10 weeks after birth from BALB/c, SPRET/EiJ, and F1 hybrids between BALB/c and SPRET/EiJ. (B) Quantification of mammary gland branching. The p-values were obtained by t-test.

Mentions: To elucidate functional mechanisms of these mammary cancer susceptible loci, we further examined whether BALB/c and SPRET/EiJ parental strains display any differences in normal mammary development. Mammary glands were collected from BALB/c and SPRET/EiJ mice at different ages, then stained with carmine alum to visualize the spatial arrangement of their ductal tree in whole mounts (Figure S4). We found that SPRET/EiJ mammary glands have fewer branches in comparison to BALB/c mammary glands (Figure 4A, Figure S4), further confirmed by quantitative analysis of the area occupied by epithelial cells (Figure S5) and branching (Figure 4B) at 10 weeks after birth. The morphology of mammary glands from F1 hybrids between BALB/c and SPRET/EiJ mimicked SPRET/EiJ (Figure 4), suggesting that the SPRET/EiJ genome is dominant for this phenotype.


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 host genetic background on mammary gland architecture.(A) Whole-mount imaging mammary gland by optical microscopy. Mammary glands were collected at 10 weeks after birth from BALB/c, SPRET/EiJ, and F1 hybrids between BALB/c and SPRET/EiJ. (B) Quantification of mammary gland branching. The p-values were obtained by t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Effect of host genetic background on mammary gland architecture.(A) Whole-mount imaging mammary gland by optical microscopy. Mammary glands were collected at 10 weeks after birth from BALB/c, SPRET/EiJ, and F1 hybrids between BALB/c and SPRET/EiJ. (B) Quantification of mammary gland branching. The p-values were obtained by t-test.
Mentions: To elucidate functional mechanisms of these mammary cancer susceptible loci, we further examined whether BALB/c and SPRET/EiJ parental strains display any differences in normal mammary development. Mammary glands were collected from BALB/c and SPRET/EiJ mice at different ages, then stained with carmine alum to visualize the spatial arrangement of their ductal tree in whole mounts (Figure S4). We found that SPRET/EiJ mammary glands have fewer branches in comparison to BALB/c mammary glands (Figure 4A, Figure S4), further confirmed by quantitative analysis of the area occupied by epithelial cells (Figure S5) and branching (Figure 4B) at 10 weeks after birth. The morphology of mammary glands from F1 hybrids between BALB/c and SPRET/EiJ mimicked SPRET/EiJ (Figure 4), suggesting that the SPRET/EiJ genome is dominant for this phenotype.

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