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NCOR2 represses MHC class I molecule expression to drive metastatic progression of breast cancer

Ticha, P.; Northey, J. J.; Kersten, K.; Velozo, H. G.; Ironside, A. J.; Zidek, M.; Drain, A.; Lakins, J. N.; Chen, Y.-Y.; Tsai, K. K.; Weaver, V. M.

2025-03-12 cancer biology
10.1101/2025.03.10.642060 bioRxiv
Show abstract

Metastatic progression depends upon the ability of disseminated tumor cells to evade immune surveillance. MHC molecule expression facilitates T cell recognition and activation to permit the eradication of metastatic tumor cells. We identified nuclear corepressor 2 (NCOR2) as a key epigenetic regulator of MHC class I molecule expression on breast tumor cells. Patients with triple negative breast cancers (TNBC) that expressed high levels of NCOR2 also exhibited reduced metastasis free survival and decreased MHC class I expression, and the metastatic lesions in patients with TNBC had high nuclear NCOR2 and reduced CD8 T cell levels and activity. Genetically and experimentally reducing NCOR2 expression in tumor cells permitted interferon gamma upregulation of MHC class I, and potentiated CD8 T cell activity and induction of apoptosis to repress metastatic progression of disseminated breast cancer cells. These studies provide evidence to support NCOR2 as a targetable epigenetic regulator of metastasis towards which therapies could be developed to reduce patient mortality.

Published in Nature Communications (predicted rank #1) · training set

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