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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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Association of plasma cytokine levels with tumor latency.The impact of plasma levels of LIX (A) and RANTES (B) on tumor latency is observed in 10 cGy treated mice, but not Sham treated mice. The p-values were obtained by log rank test.
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f3: Association of plasma cytokine levels with tumor latency.The impact of plasma levels of LIX (A) and RANTES (B) on tumor latency is observed in 10 cGy treated mice, but not Sham treated mice. The p-values were obtained by log rank test.

Mentions: Given the strong representation of cytokine signaling pathways within the identified stromal genetic loci, we assessed the association of plasma cytokine levels with tumor latency by dividing mice into three groups based on plasma cytokine levels (low = bottom third, moderate = middle third, and high = top third). In sham-treated F1Bx mice, plasma levels of eotaxin at 6 hrs after treatment and IL-1A at 15 weeks after treatment were significantly associated with tumor latency (Figure S2). In 10 cGy-treated F1Bx mice, plasma levels of two cytokines (G-CSF and IL-13) at the early time point and three cytokines (IP10, LIX, and RANTES) at the later time point were significantly associated with tumor latency (Figure 3, Figure S3). For example, mice with high levels of LIX (Figure 3A) or RANTES (Figure 3B) developed tumors significantly later than those with low levels. These data are consistent with the demonstration that 10 cGy treatment significantly increases RANTES levels (Chang et al., submitted).


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)

Association of plasma cytokine levels with tumor latency.The impact of plasma levels of LIX (A) and RANTES (B) on tumor latency is observed in 10 cGy treated mice, but not Sham treated mice. The p-values were obtained by log rank test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Association of plasma cytokine levels with tumor latency.The impact of plasma levels of LIX (A) and RANTES (B) on tumor latency is observed in 10 cGy treated mice, but not Sham treated mice. The p-values were obtained by log rank test.
Mentions: Given the strong representation of cytokine signaling pathways within the identified stromal genetic loci, we assessed the association of plasma cytokine levels with tumor latency by dividing mice into three groups based on plasma cytokine levels (low = bottom third, moderate = middle third, and high = top third). In sham-treated F1Bx mice, plasma levels of eotaxin at 6 hrs after treatment and IL-1A at 15 weeks after treatment were significantly associated with tumor latency (Figure S2). In 10 cGy-treated F1Bx mice, plasma levels of two cytokines (G-CSF and IL-13) at the early time point and three cytokines (IP10, LIX, and RANTES) at the later time point were significantly associated with tumor latency (Figure 3, Figure S3). For example, mice with high levels of LIX (Figure 3A) or RANTES (Figure 3B) developed tumors significantly later than those with low levels. These data are consistent with the demonstration that 10 cGy treatment significantly increases RANTES levels (Chang et al., submitted).

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