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bioRxiv · 10.1101/2025.03.10.642060

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.
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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.

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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. NCOR2 represses MHC class I molecule expression to drive metastatic progression of breast cancer. https://doi.org/10.1101/2025.03.10.642060

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