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Updated: Jan 15, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Identification of susceptibility loci using a novel murine model for triple-negative breast cancer
Minjeong Kim1, Logan G McGrath1, Zeid T Mustafa1
1Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, United States.
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.
Insights
Researchers developed a new mouse model for triple-negative breast cancer (TNBC) to find genetic causes. This model helped identify genes linked to TNBC progression, offering potential new therapeutic targets for this aggressive cancer.
Area of Science:
- Genetics
- Oncology
- Animal Models
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited targeted treatment options.
- Identifying genetic modifiers is crucial for understanding TNBC pathogenesis and developing novel therapies.
Purpose of the Study:
- To create and utilize a genetically diverse murine model for identifying genetic modifiers of TNBC.
- To map quantitative trait loci (QTLs) associated with TNBC traits and identify candidate genes.
Main Methods:
- Generation of a BXD recombinant inbred hybrid mouse model incorporating the C3(1)-T-antigen transgene for spontaneous TNBC development.
- Systematic crossing of C3Tag mice with sequenced BXD strains to introduce genetic heterogeneity.
- Quantitative trait loci (QTL) mapping to identify genomic regions influencing TNBC traits like tumor latency, multiplicity, and survival.
Main Results:
- Significant heritability of TNBC traits including tumor latency, multiplicity, and survival was observed in the BXD-BC model.
- Genetic loci on chromosomes 16 and 10 were associated with tumor multiplicity and latency, respectively.
- Candidate genes Gns, Rassf3, and Tbc1d30 were prioritized, with higher expression correlating with poorer survival in human breast cancer patients.
Conclusions:
- The developed BXD-BC model offers robust genetic heterogeneity for identifying conserved TNBC modifiers.
- The identified candidate genes (Gns, Rassf3, Tbc1d30) represent potential therapeutic targets for TNBC.
- This study provides a valuable platform for further research into the genetic basis of breast cancer.
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