NCOR2 represses MHC class I molecule expression to drive metastatic progression of breast cancer
- Pavla Ticha
- Jason J. Northey
- Radhika Narain
- Shivang Sharma
- Johnathon N. Lakins
- Hugo Gonzalez
- Kelly Kersten
- Alastair J. Ironside
- Allison P. Drain
- Martin Zidek
- Kelvin K. Tsai
- Yunn-Yi Chen
- Eugene Shenderov
- Valerie M. Weaver
2026-05-05
Metastatic progression depends upon the ability of disseminated tumor cells to evade immune surveillance. Major Histocompatibility Complex (MHC)-mediated antigen presentation facilitates T cell-dependent eradication of metastatic tumor cells. Here, we show that nuclear corepressor 2 (NCOR2) is an epigenetic regulator of MHC class I molecule presentation on breast tumor cells. Patients with triple negative breast cancer (TNBC) that express high levels of NCOR2 also exhibit reduced metastasis-free survival and decreased MHC class I expression, and the metastatic lesions in patients with TNBC have high nuclear NCOR2 and reduced Cluster of Differentiation (CD)8 + T cells. Reducing NCOR2 expression or preventing its interaction with Histone Deacetylase, HDAC3, enhances innate immune cell recruitment and activity, and elevates MHC class I levels on disseminated cancer cells to potentiate CD8 + T cell activity and apoptosis induction that prevents metastatic progression. The studies provide evidence to support NCOR2 as a targetable epigenetic regulator of metastasis towards which therapies could be developed to reduce patient mortality.