EZH2 directs HER2+ breast cancer progression through the modulation of epithelial plasticity.

Breast cancer remains a leading cause of death among women, with the HER2+ subtype being particularly aggressive due to acquired resistance to HER2-targeted therapies. Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2, represses the expression of genetic programs crucial for differentiation, proliferation, and apoptosis. To investigate the role of EZH2 in HER2+ tumor progression, we crossed a genetically engineered mouse model of HER2-driven breast cancer with a conditional Ezh2 knockout strain and showed that Ezh2 is essential for accelerating tumor initiation and metastatic dissemination. Combined bulk and single cell RNA sequencing analyses revealed a significant downregulation of basal cell populations in the absence of Ezh2, and an upregulation of luminal progenitor cell populations, driven by crucial transcription factors such as Esr1. Further, inhibition of EZH2 in vitro resulted in increased expression of ER in HER2+ human breast cancer cell lines and conferred sensitivity to Tamoxifen. These findings demonstrate that EZH2 dictates cancer plasticity and provides rationale for combining EZH2 inhibitors with endocrine therapies to improve HER2+ breast cancer outcomes.