Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment.
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.
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Pengju
P
Zhang
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Alvin
A
Lo
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Yurong
Y
Huang
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Ge
G
Huang
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Guozhou
G
Liang
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Joni
J
Mott
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Gary H
GH
Karpen
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Eleanor A
EA
Blakely
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Mina J
MJ
Bissell
NYU School of Medicine, New York, NY 10016.
Mary Helen
MH
Barcellos-Hoff
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Antoine M
AM
Snijders
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Jian-Hua
JH
Mao
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D012307:Risk Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics*
D016207:Cytokines; D053773:Transforming Growth Factor beta1