Identification of actionable targets for breast cancer intervention using a diversity outbred mouse model
Jennifer B Jacob1, Kuang-Chung Wei1, Gerold Bepler1
1Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA.
Abstract:
HER2-targeted therapy has improved breast cancer survival, but treatment resistance and disease prevention remain major challenges. Genes that enable HER2/Neu oncogenesis are the next intervention targets. A bioinformatics discovery platform of HER2/Neu-expressing Diversity Outbred (DO) F1 Mice was established to identify cancer-enabling genes. Quantitative Trait Loci (QTL) associated with onset ages and growth rates of spontaneous mammary tumors were sought. Twenty-six genes in 3 QTL contain sequence variations unique to the genetic backgrounds that are linked to aggressive tumors and 21 genes are associated with human breast cancer survival. Concurrent identification of TSC22D3, a transcription factor, and its target gene LILRB4, a myeloid cell checkpoint receptor, suggests an immune axis for regulation, or intervention, of disease. We also investigated TIEG1 gene that impedes tumor immunity but suppresses tumor growth. Although not an actionable target, TIEG1 study revealed genetic regulation of tumor progression, forming the basis of the genetics-based discovery platform.
Insights
Researchers identified novel genes driving HER2-positive breast cancer using a bioinformatics platform in mice. These genes offer new targets for overcoming treatment resistance and improving patient survival.
Area of Science:
- Oncology
- Genetics
- Bioinformatics
Background:
- HER2-targeted therapy significantly improved breast cancer survival.
- Treatment resistance and disease prevention remain critical challenges in HER2-positive breast cancer.
- Identifying genes that drive HER2/Neu oncogenesis is crucial for developing new interventions.
Purpose of the Study:
- To establish a bioinformatics discovery platform using HER2/Neu-expressing Diversity Outbred (DO) F1 mice.
- To identify novel cancer-enabling genes associated with mammary tumor development and progression.
- To uncover potential therapeutic targets for HER2-positive breast cancer.
Main Methods:
- Utilized a bioinformatics discovery platform with HER2/Neu-expressing DO F1 mice.
- Performed Quantitative Trait Loci (QTL) analysis to identify genes linked to tumor onset age and growth rates.
- Analyzed sequence variations in identified QTL genes and correlated them with aggressive tumors and human breast cancer survival data.
Main Results:
- Identified 26 genes within 3 QTL containing unique sequence variations linked to aggressive tumors.
- Found 21 genes associated with human breast cancer survival.
- Discovered a potential immune axis involving transcription factor TSC22D3 and its target gene LILRB4.
- Investigated TIEG1 gene's role in impeding tumor immunity but suppressing tumor growth.
Conclusions:
- The developed genetics-based discovery platform is effective for identifying cancer-enabling genes.
- Identified genes, including TSC22D3 and LILRB4, suggest novel immune-related intervention strategies for breast cancer.
- The study provides a foundation for future genetic-based approaches to understand and combat breast cancer progression.
