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.