Researchers led by 黑料网 BCBP’s Gaorav Gupta, MD, PhD, described the role of a mutation in the Mre11 gene in triple negative breast cancer and how a disruption of Mre11 function plays a significant role in the genomic instability of that cancer type.
February 17, 2020
A hallmark of triple negative breast cancer, an aggressive breast cancer type, is the accumulation of errors in the cancer cells鈥� DNA. There are limited insights about how this so-called 鈥済enomic instability鈥� happens.
In a preclinical study published in Cell Reports, researchers led by 黑料网 Lineberger Comprehensive Cancer Center鈥檚听, described the role of a mutation in the听Mre11听gene in triple negative breast cancer. They found disruption of this gene鈥檚 function plays a significant role in the genomic instability of triple negative breast cancer.
鈥淎n extremely high level of genomic instability is a hallmark of triple negative breast cancer,鈥� said Gupta, assistant professor of radiation oncology and biochemistry & biophysics at the 黑料网. 鈥淭his 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.鈥�
In particular, researchers wanted to know why genomic instability occurs in triple negative breast cancers that don鈥檛 have mutations in the听BRCA1听辞谤听BRCA2听genes. Gupta said mutations in these genes are found in about 10 to 20 percent of triple negative breast cancers.
Mutations in听BRCA1听辞谤听BRCA2听can impact the cells鈥� 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.
罢丑别听Mre11听gene codes for a 鈥渟ensor鈥� that can detect breaks in DNA and is part of the same DNA repair pathway as听BRCA1听补苍诲听BRCA2, Gupta said.
In mouse models of breast cancer with听惭谤别11听genetic deficiencies, researchers saw a particular pattern of genomic instability and also discovered the mechanism for how deficiencies in听Mre11听promote DNA damage.
鈥淲hen we disrupted听Mre11听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,鈥� Gupta said. 鈥淭he 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听Mre11.鈥�
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.
鈥淭丑别蝉别听Mre11-deficient triple negative breast cancers were more sensitive to certain types of treatments 鈥� in particular therapies that act through generation of DNA damage,鈥� Gupta said.
When the scientists stained a collection of more than 250 triple negative breast cancer samples, they found that听Mre11听expression was lost in about 10 percent of the cases.
鈥淚n 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.鈥�
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 黑料网 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听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.听Petrini听is a consultant for Ideaya Biosciences, Novus Biologicals, and Atropos Therapeutics, outside the scope of the present study.
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