Does a Certain Protein Complex Contribute to Endocrine Resistance in Breast Cancer?

By: Joshua D. Madera, MS
Posted: Friday, March 3, 2023

For patients with advanced breast cancer, the chromatin-modifying protein complex CoREST may prove to be a novel therapeutic target, according to a study published in Nature Structural & Molecular Biology. The involvement of CoREST in building resistance to endocrine therapies, tumorigenesis, and cellular plasticity may optimize its role as a therapeutic target, according to Lluis Morey, PhD, of the Sylvester Comprehensive Cancer Center, Miami, and colleagues.

“By targeting this epigenetic machinery, specifically the CoREST complex, we could potentially offer new treatments for these challenging cancers. We hope these discoveries will pave the way for new therapeutic options for women with incurable breast cancers,” stated coauthor Liliana Garcia-Martinez, PhD student in Dr. Morey’s lab, in an institutional press release.

The CoREST complex modifies genetic expression through epigenetic modifications. Specifically, it alters genetic regulation in oncogenes and genes associated with cancer metastasis by removing methyl and acetyl groups from histones, increasing the risk of carcinogenesis. This role is also important in its impact on the estrogen pathway, since these modifications increase cells’ resistance to endocrine-directed therapies. The CoREST protein subunit LSD1 plays a critical role in maintaining this drug therapy resistance, according to the authors.

Additional analyses revealed a signature of genes that are directly regulated by the CoREST complex in patients who developed drug therapy resistance. These findings imply that inhibition of the CoREST complex may lead to inhibition of endocrine resistance and perhaps responsiveness to drug therapies for breast cancer. Moreover, preliminary findings in animal models have indicated that the use of pharmacotherapies targeting protein subunits of CoREST including LSD1 and histone deacetylases significantly decreased patients’ tumor burden.

Disclosure: The study authors reported no conflicts of interest.

Nature Structural & Molecular Biology

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