Estrogen receptor beta repurposes EZH2 to suppress oncogenic NFκB/p65 signaling in triple negative breast cancer

Triple Negative Breast Cancer (TNBC) accounts for 15-20% of all breast cancer cases, yet is responsible for a disproportionately high percentage of breast cancer mortalities. Thus, there is an urgent need to identify novel biomarkers and therapeutic targets based on the molecular events driving TNBC pathobiology. Estrogen receptor beta (ER beta) is known to elicit anti-cancer effects in TNBC, however its mechanisms of action remain elusive. Here, we report the expression profiles of ER beta and its association with clinicopathological features and patient outcomes in the largest cohort of TNBC to date. In this cohort, ER beta was expressed in approximately 18% of TNBCs, and expression of ERI3 was associated with favorable clinicopathological features, but correlated with different overall survival outcomes according to menopausal status. Mechanistically, ER beta formed a co-repressor complex involving enhancer of zeste homologue 2/polycomb repressive complex 2 (EZH2/PRC2) that functioned to suppress oncogenic NF kappa B/RELA (p65) activity. Importantly, p65 was shown to be required for formation of this complex and for ERP-mediated suppression of TNBC. Our findings indicate that ER beta+ tumors exhibit different characteristics compared to ER beta- tumors and demonstrate that ER beta functions as a molecular switch for EZH2, repurposing it for tumor suppressive activities and repression of oncogenic p65 signaling.

Automated summary

This study reported the expression profiles of ER beta in the largest cohort of TNBC to date and its association with clinicopathological features and patient outcomes. ER beta was found to be expressed in approximately 18% of TNBCs and its expression was associated with favorable clinicopathological features. Mechanistically, ER beta formed a co-repressor complex to suppress oncogenic NF kappa B/RELA (p65) activity.