Biological Markers Identified for Triple Negative Breast Cancer

Triple negative breast cancer, or TNBC, is one of the most challenging forms of breast cancer to be treated. Standard chemotherapy drugs, such as carboplatin, and radiation therapies often have little to no effect on patients, causing a push in research to find more effective treatment strategies. That’s why researchers at the Baylor College of Medicine, the Broad Institute of MIT and Harvard, and Washington University in St. Louis all teamed up to identify new biological markers of TNBC.

Their work, recently published in the journal Cancer Discovery, included advanced analytic and proteogenomic techniques to further probe tumor cell biopsies taken from TNBC patients prior to treatment with carboplatin and docetaxel combination chemotherapy. To further investigate these cancerous tissue samples, the team utilized a combination of DNA and RNA sequencing, mass spectrometry-based proteomics, and phosphoproteomic analyses. The results described complete molecular “portraits” of treatment-responsive versus treatment-resistant tumors.

“The proteomic analysis of pretreatment biopsies uniquely revealed metabolic pathways that were associated with resistance to treatment, including fatty acid metabolism,” says Dr. Meenakshi Anurag, assistant professor of medicine at the Lester and Sue Smith Breast Center at Baylor. Specifically, the team noted that chemotherapy sensitivity was marked by higher DNA repair signatures, interferon gamma signaling, and immune checkpoint components. These findings suggest a potential multi-omics approach for chemotherapy.

By analyzing these samples on a chromosomal level, the team also found that a deletion on chromosome 19, located within region 19q13.31-33, was correlated with resistance to chemotherapy treatment. Specifically, one gene deletion of DNA ligase LIG1 was found to suppress genes at both the mRNA and protein levels consistently. LIG1 is a critical component of the lagging strand that connects small DNA segments, or Okazaki fragments, during DNA synthesis.

“LIG1 loss was also associated with poor prognosis in other cancer types, showing that this deletion has broader clinical significance,” says Anurag, a member of Baylor’s Dan L Duncan Comprehensive Cancer Center. Currently, the researchers are working on clinical grade assays to confirm that LIG1 loss can be safely used to direct carboplatin chemotherapy in TNBC.

Though lagging-strand synthesis components are generally considered essential to cellular survival, in these findings, the reduction in the level of these enzymes resulted in significant chromosomal instability within multiple cancer types and selective carboplatin resistance in TNBC. In the future, mechanistic studies could examine the details of genome destabilization and how to effectively treat tumors with LIG1 deletions.

“This is an exciting result that is a testament to the remarkably close collaboration between patients, oncology care teams and laboratory scientists. In our view, proteogenomic analyses should be routine in clinical trials to discover clinically useful biomarkers, new biological insight and therapeutic hypotheses,” said Dr. Shankha Satpathy, co-author of the study and senior group leader at in the Proteomics Platform at Broad.