# Identification of susceptibility loci using a novel murine model for triple-negative breast cancer

## TL;DR

A new mouse model for triple-negative breast cancer reveals genetic loci and genes linked to tumor traits and poor patient survival.

## Contribution

A novel murine model with genetic diversity identifies conserved TNBC modifiers and potential therapeutic targets.

## Key findings

- Loci on chromosomes 16 and 10 are associated with tumor multiplicity and latency in TNBC.
- Genes GNS, RASSF3, and TBC1D30 are linked to poor survival in breast cancer patients.
- The BXD-BC model enables identification of heritable tumor traits and genetic modifiers.

## Abstract

Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer (BC) with few targeted therapies. To identify novel genetic modifiers of TNBC, we created a murine model incorporating high levels of genetic and phenotypic diversity. C3(1)-T-antigen (“C3Tag”) mice, which develop spontaneous basal-like TNBC tumors, were systematically crossed with a large set of sequenced BXD recombinant inbred strains to produce isogenic hybrids segregating for C3Tag. The severity of TNBC traits including tumor latency, multiplicity, and survival was highly variable and heritable. We mapped modifiers of TNBC and identified loci on chromosomes 16 and 10 associated with tumor multiplicity and latency, respectively. Candidate genes were prioritized including a lysosomal enzyme involved in cell proliferation, Gns; tumor suppressor Rassf3; and Rab-modifying Tbc1d30. In tumors from BC patients, higher GNS, RASSF3, and TBC1D30 expression associated with poor overall survival. In sum, we developed a clinically relevant, BXD-BC model which provides robust genetic heterogeneity enabling the identification of conserved modifiers and mediators of BC.

A novel mouse model was developed for a target audience of cancer genetics researchers. Cancer-prone C3(1)-T-antigen mice were crossed with genetically diverse BXD recombinant inbred strains. This clinically relevant model is useful because it has publicly available data through GeneNetwork. Findings have uncovered genes to guide future TNBC treatments. Hybrids showed significantly heritable variation in tumor latency, multiplicity, and survival. Genetic modifiers impacting tumor traits were mapped with loci identified on chromosomes 16 and 10 linked to BC tumor onset and growth. Key conserved genes-GNS, RASSF3, and TBC1D30—correlated with poor survival in BC patients.