Screening of organoids derived from patients with breast cancer implicates the repressor NCOR2 in cytotoxic stress response and antitumor immunity

Weaver and colleagues use breast cancer patient-derived organoids and mouse models to find an inhibitory role for the nuclear repressor NCOR2 in chemotherapy response and antitumor immunity, which can be targeted by blocking NCOR2-HDAC3 interaction. Resistance to antitumor treatment contributes to patient mortality. Functional proteomic screening of organoids derived from chemotherapy-treated patients with breast cancer identified nuclear receptor corepressor 2 (NCOR2) histone deacetylase as an inhibitor of cytotoxic stress response and antitumor immunity. High NCOR2 in the tumors of patients with breast cancer predicted chemotherapy refractoriness, tumor recurrence and poor prognosis. Molecular studies revealed that NCOR2 inhibits antitumor treatment by regulating histone deacetylase 3 (HDAC3) to repress interferon regulatory factor 1 (IRF-1)-dependent gene expression and interferon (IFN) signaling. Reducing NCOR2 or impeding its epigenetic activity by modifying its interaction with HDAC3 enhanced chemotherapy responsiveness and restored antitumor immunity. An adeno-associated viral NCOR2-HDAC3 competitor potentiated chemotherapy and immune checkpoint therapy in culture and in vivo by permitting transcription of IRF-1-regulated proapoptosis and inflammatory genes to increase IFN-gamma signaling. The findings illustrate the utility of patient-derived organoids for drug discovery and suggest that targeting stress and inflammatory-repressor complexes such as NCOR2-HDAC3 could overcome treatment resistance and improve the outcome of patients with cancer.

Automated summary

The study demonstrates the inhibitory role of nuclear repressor NCOR2 in chemotherapy response and antitumor immunity using breast cancer patient-derived organoids and mouse models. Blocking NCOR2-HDAC3 interaction provides a potential therapeutic target. The findings highlight the importance of targeting stress and inflammatory-repressor complexes, such as NCOR2-HDAC3, to overcome treatment resistance and improve outcomes for cancer patients.