It is called MRE11 and it is a protein already known to recognize DNA damage: a new study published in Nature has however revealed that it is also the “key” to an immune response pathway capable of suppressing the formation of breast tumors.
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There seems to be a “key” to preventing breast cancer: it is la protein MRE11, an enzyme present in the nucleus of human cells, already known to recognize DNA damage. However, what had not yet been understood is that this same protein may also have an essential role in suppressing the formation of breast tumors.
This was discovered by the research group led by Professor Gaorav Gupta of the Department of Radiation Oncology at the School of Medicine of the American University of North Carolina at Chapel Hill (UNC) who, in a study just published in Natureshowed for the first time that the MRE11 protein is crucial in the activation of an immune response pathway which identifies cells with damaged DNA and eliminates them from the body.
The MRE11 protein, the scholars explain, also acts “unblocking” the cGAS/STING pathwaya pathway of the innate immune system that is normally kept in check to prevent excessive inflammation in healthy conditions.
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“Our findings suggest that loss of this pathway may be what allows breast cancer cells to resist high levels of DNA damage without being recognized by the immune system” said Professor Gupta, who is also a member of the Lineberger Comprehensive Cancer Center, UNC’s cancer research and treatment center. We are very interested in identifying ways to reactivate this pathway to treat and potentially even prevent the development of cancer”.
The MRE11 protein may be the “key” to preventing the development of breast cancer
Professor Gupta’s team’s study sheds light on how cancer cells avoid being detected by the immune system, despite suffering DNA damage during cell division. The research, specifically, indicates that breast cancer cells can “lock in” to their advantage the cGAS-STING pathway, which allows them to escape immune detection.
This block insists on an enzyme, known as cyclic synthase GMP-AMP (cGAS), recognized as a messenger of the immune system, which is normally in a dormant state, being activated only when absolutely necessary. “It is in an ‘off’ state because it has a much stronger affinity for histone molecules, which are proteins around which our DNA is packaged, than the DNA itself – specified Gupta –. You can think of cGAS as being blocked due to its binding to histones, unable to do its job of recognizing DNA unless it is freed by some key”.
Based on previous research published in Sciencethe team hypothesized that the MRE11 protein might be the key that releases cGAS from its histone prison. And, indeed, the researchers found that MRE11, while recognizing and binding to damaged DNA, simultaneously releases cGAS from histones.
The interaction between MRE11 cGAS also activates a specific form of cell death, known as necroptosis / Credit: Min-Guk Cho et al., Nature 2024.
The team also found that the interaction between MRE11 and cGAS triggers a specific form of cell death called necroptosis. This specific form of cell death activates the immune system, providing a powerful mechanism for elimination damaged precancerous cells before they progress to cancer.
“Linking MRE11 and cGAS to the activation of necroptosis is a very effective way to suppress tumor formation – added Gupta –. When MRE11 and cGAS are activated by a damaged precancerous cell, they cooperate to trigger a form of cell death which boosts the immune systemto help the body eliminate cells before they become cancerous”.
The future of breast cancer prevention and treatment
Reactivation of the cGAS-STING pathway through MRE11 opens up new possibilities for targeted therapies, offering hope in development of prevention strategies and more effective breast cancer treatments. Currently, Gupta and his colleagues at the Lineberger Comprehensive Cancer Center are already taking action a further step forward in researchactively enrolling patients in a clinical trial studying the combination of radiation and immunotherapy in the treatment of certain types of breast cancer.
With this new information about the cGAS-STING pathway, scientists will now observe whether the newly identified pathway is more or less responsive to these therapies or whether other specific therapies can engage this pathway and thus lead to better clinical outcomes.