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Updated: May 16, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic
David W Craig1, Joyce A O'Shaughnessy, Jeffrey A Kiefer
1Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
Abstract:
Triple-negative breast cancer (TNBC) is characterized by the absence of expression of estrogen receptor, progesterone receptor, and HER-2. Thirty percent of patients recur after first-line treatment, and metastatic TNBC (mTNBC) has a poor prognosis with median survival of one year. Here, we present initial analyses of whole genome and transcriptome sequencing data from 14 prospective mTNBC. We have cataloged the collection of somatic genomic alterations in these advanced tumors, particularly those that may inform targeted therapies. Genes mutated in multiple tumors included TP53, LRP1B, HERC1, CDH5, RB1, and NF1. Notable genes involved in focal structural events were CTNNA1, PTEN, FBXW7, BRCA2, WT1, FGFR1, KRAS, HRAS, ARAF, BRAF, and PGCP. Homozygous deletion of CTNNA1 was detected in 2 of 6 African Americans. RNA sequencing revealed consistent overexpression of the FOXM1 gene when tumor gene expression was compared with nonmalignant breast samples. Using an outlier analysis of gene expression comparing one cancer with all the others, we detected expression patterns unique to each patient's tumor. Integrative DNA/RNA analysis provided evidence for deregulation of mutated genes, including the monoallelic expression of TP53 mutations. Finally, molecular alterations in several cancers supported targeted therapeutic intervention on clinical trials with known inhibitors, particularly for alterations in the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways. In conclusion, whole genome and transcriptome profiling of mTNBC have provided insights into somatic events occurring in this difficult to treat cancer. These genomic data have guided patients to investigational treatment trials and provide hypotheses for future trials in this irremediable cancer.
Insights
Genomic analysis of metastatic triple-negative breast cancer (TNBC) reveals key mutations and gene expression patterns. These findings offer insights for developing targeted therapies and guiding patients to clinical trials for this aggressive cancer.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Triple-negative breast cancer (TNBC) lacks standard targeted therapies and has a poor prognosis, especially in its metastatic form (mTNBC).
- Recurrence rates are high after initial treatment, highlighting the need for novel therapeutic strategies.
Purpose of the Study:
- To perform whole genome and transcriptome sequencing on prospective metastatic TNBC samples.
- To identify somatic genomic alterations and gene expression patterns that could inform targeted therapy development.
Main Methods:
- Whole genome and transcriptome sequencing of 14 prospective mTNBC patient samples.
- Analysis of somatic mutations, structural variants, and gene expression profiles.
- Integrative DNA/RNA analysis to understand gene deregulation.
Main Results:
- Cataloged somatic genomic alterations, identifying frequently mutated genes (e.g., TP53, LRP1B, RB1).
- Detected focal structural events involving genes like CTNNA1, PTEN, and FGFR1.
- Observed consistent overexpression of FOXM1 and identified patient-specific expression patterns; linked alterations to potential targeted therapies in RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways.
Conclusions:
- Whole genome and transcriptome profiling provide crucial insights into the molecular landscape of mTNBC.
- Genomic findings support patient enrollment in targeted therapy clinical trials and generate hypotheses for future research in this challenging cancer.
