Breast cancer (BC) is the most common cancer and the second cause of death in US women. Our lack of understanding of how genetic variants affect molecular mechanisms that mediate BC aggression poses a substantial obstacle to advancements in cancer diagnosis and therapy. To examine genetic variants on BC traits, a novel murine model was created with robust phenotypic and genomic variation. The FVB C3(1)-T-antigen (“C3Tag”) mouse develops spontaneous tumors in the mammary glands of female mice with a mean latency of 4-5 months of age. This genetically engineered mouse model (GEMM) is well established to resemble human basal-like TNBC. TNBC is an aggressive subtype with few clinical approaches and poor patient outcomes. Thus, to model human heterogeneity in BC outcomes, we systematically crossed the C3Tag GEMM into the BXD recombinant inbred family – the largest and best characterized genetic reference population. The new model is termed “BXD-BC” and F1 hybrids of the cross have isogenic genomes that are reproducible. BXD-BCs are a potent tool to determine the impact of genetic modifiers on BC tumor traits. We hypothesized that examination of BXD-BC GEMMs will enable the identification of susceptibility loci, candidate genes, and molecular networks that underlie variation of multiple BC phenotypes. Using N=29 BXD-BC strains, we demonstrated significant heritable variations in the severity of TNBC characteristics such as tumor latency, multiplicity, and survival. Interestingly, 2 BXD-BC strains never developed tumors out to 1 year of age. Thus, BXD-BC strains demonstrate variance in cancer susceptibility and progression compared to the parent C3Tag GEMM, indicating the presence of genetic modifiers. Through an unbiased systematic quantification of breast cancer severity across BXD-BC hybrids, we identified several significant quantitative trait loci (QTL) and candidate genes for specific tumor traits. In combination with public human GWAS datasets, we defined syntenic regions, candidate genes, and underlying networks through cross-species systems genetics analyses to demonstrate the translational validity of conserved, biologically relevant, and targetable candidates. Our findings suggest conserved candidates predicting TNBC patient survival. In sum, the BXD-BC resource is an innovative, reliable, and robust preclinical model that reflects robust genetic heterogeneity. Using cutting edge systems genetics, we have identified genetic modifiers of BC phenotypic variation that could be targeted to advance therapeutic limitations or as biomarkers of risk or response to therapy.### Competing Interest StatementThe authors have declared no competing interest.

How lifespan and body weight vary as a function of diet and genetic differences is not well understood. Here we quantify the impact of differences in diet on lifespan in a genetically diverse family of female mice, split into matched isogenic cohorts fed a low-fat chow diet (CD, n = 663) or a high-fat diet (HFD, n = 685). We further generate key metabolic data in a parallel cohort euthanized at four time points. HFD feeding shortens lifespan by 12%: equivalent to a decade in humans. Initial body weight and early weight gains account for longevity differences of roughly 4–6 days per gram. At 500 days, animals on a HFD typically gain four times as much weight as control, but variation in weight gain does not correlate with lifespan. Classic serum metabolites, often regarded as health biomarkers, are not necessarily strong predictors of longevity. Our data indicate that responses to a HFD are substantially modulated by gene-by-environment interactions, highlighting the importance of genetic variation in making accurate individualized dietary recommendations. Roy et al. quantify the impact of a high-fat diet across genetically diverse strains of mice, revealing a generally negative effect on lifespan but also a wide variability.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease that may progress to fibrosis and significant risk of death. HP develops following repeated exposures to inhaled environmental antigens; however, only a fraction of the exposed population develops the disease, suggesting that host genetics contribute to disease susceptibility. We used the BXD family of mice with the Saccharopolyspora rectivirgula (SR) model of HP to investigate the role of genetics in susceptibility to HP. The BXD family is derived from a B6 mother and a D2 father and has been used to map susceptibility loci to numerous diseases. B6, D2, and BXD progeny strains were exposed to SR for 3 wk, and the development of HP was monitored. The B6 and D2 strains developed alveolitis; however, the cellular composition was neutrophilic in the D2 strain and more lymphocytic in the B6 strain. Hematoxylin-eosin staining of lung sections revealed lymphoid aggregates in B6 lungs, whereas D2 lungs exhibited a neutrophilic infiltration. Twenty-eight BXD strains of mice were tested, and the results reveal significant heritable variation for numbers of CD4+ or CD8+ T cells in the air spaces. There was significant genetic variability for lymphoid aggregates and alveolar wall thickening. We mapped a significant quantitative trait locus (QTL) on chromosome 18 for CD8+CD69+ T cells that includes cadherin 2 (Cdh2), an excellent candidate gene associated with epithelial-mesenchymal transition, which is upregulated in lungs of strains with HP. These results demonstrate that the BXD family is a valuable and translationally relevant model to identify genes contributing to HP and to devise early and effective interventions.

Diet and environment profoundly modulate lifespan. We measured longevity as a function of diet and weight gain across a genetically diverse family of mice. We followed 1348 females from two parental strains—C57BL/6J and DBA/2J—and 146 cohorts of BXD isogenic progeny strains ( n = 73) across their lifespan on a low fat chow diet (CD, 18% calories from fat) and on a high fat diet (HFD, 60% calories from fat). On average, HFD shortens lifespan by 85 days or 12%, roughly equivalent to an 8–10 year decrease in humans. However, strain variation in the response of diet on longevity is remarkably high, ranging from a longevity loss of 54% in BXD65 to a gain of 37% in BXD8. Baseline weights and early weight gain are both associated with a mean decrease in longevity of ∼4 days/g. By 500 days-of-age, cases fed HFD gained four times as much weight as control on average. However, strain-specific variation was substantial, thus weight gain did not correlate well with lifespan. In summary, high fat had a strong negative effect on longevity, but genetic interactions effects were even stronger. This highlights the unequivocal importance of genetic differences in making dietary recommendations.