CHAPEL HILL – A hallmark of triple negative breast cancer, an aggressive breast cancer type, is the accumulation of errors in the cancer cells’ DNA. There are limited insights about how this so-called “genomic instability” happens.
In a preclinical study published in Cell Reports, researchers led by UNC Lineberger Comprehensive Cancer Center’s Gaorav Gupta, MD, PhD, described the role of a mutation in the Mre11 gene in triple negative breast cancer. They found disruption of this gene’s function plays a significant role in the genomic instability of triple negative breast cancer.
“An extremely high level of genomic instability is a hallmark of triple negative breast cancer,” said Gupta, assistant professor of radiation oncology and biochemistry & biophysics at the UNC School of Medicine. “This hallmark feature is very poorly understood, however. We wanted to ask whether mutations or alterations in DNA repair pathways may explain why they have such an unstable genome.”
In particular, researchers wanted to know why genomic instability occurs in triple negative breast cancers that don’t have mutations in the BRCA1 or BRCA2 genes. Gupta said mutations in these genes are found in about 10 to 20 percent of triple negative breast cancers.
Mutations in BRCA1 or BRCA2 can impact the cells’ ability to repair breaks in their DNA. But in the absence of these mutations, researchers wanted to know how genetic errors start to accumulate and continue over time.
The Mre11 gene codes for a “sensor” that can detect breaks in DNA and is part of the same DNA repair pathway as BRCA1 and BRCA2, Gupta said.
In mouse models of breast cancer with Mre11 genetic deficiencies, researchers saw a particular pattern of genomic instability and also discovered the mechanism for how deficiencies in Mre11 promote DNA damage.
“When we disrupted Mre11 in models of triple negative breast cancer, these cancerous cells were able to proliferate much faster, and they were accumulating DNA damage at a much faster rate,” Gupta said. “The breast cancers that emerged in this model also exhibited a unique pattern of genomic instability that we were able to tie to this deficiency in Mre11.”
They also found triple negative breast cancers were extremely sensitive to certain drugs that act through the generation of DNA damage, like chemotherapy, and inhibitors that impair DNA repair.
“These Mre11-deficient triple negative breast cancers were more sensitive to certain types of treatments – in particular therapies that act through generation of DNA damage,” Gupta said.
When the scientists stained a collection of more than 250 triple negative breast cancer samples, they found that Mre11 expression was lost in about 10 percent of the cases.
“In the future, we would like to explore whether patients with Mre11 deficient tumors could be treated with less chemotherapy or with a targeted therapy in order to reduce toxicity and achieve higher levels of cure.”
In addition to Gupta, other authors include Katerina D. Fagan-Solis, Dennis A. Simpson, Rashmi J. Kumar, Luciano Martelotto, Lisle E. Mose, Naim U. Rashid, Alice Y. Ho, Simon N. Powell, Y. Hannah Wen, Joel S. Parker, Jorge S. Reis-Filho, and John H.J. Petrini.
The study was supported by Susan G. Komen, the National Cancer Institute, the National Institutes of Health, the UNC Lineberger core grant, the Memorial Sloan Kettering Cancer Center core grant, and the University Cancer Research Fund. Individual researchers were supported by the Breast Cancer Research Foundation and the Ruth L. Kirchstein National Research Service Award Individual Postdoctoral Fellowship.
Conflicts of interest: Gupta has ownership interests, including patents, in and is a consultant/advisory board member for Naveris Inc. outside the scope of the present study.
Reis-Filho reports personal/consultancy fees from VolitionRx, Page.AI, Goldman Sachs, Grail, Ventana Medical Systems, Invicro, Roche Diagnostics, and Genentech, outside the scope of the present study. Petrini is a consultant for Ideaya Biosciences, Novus Biologicals, and Atropos Therapeutics, outside the scope of the present study.