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

## TL;DR

EZH2 promotes aggressive HER2+ breast cancer by maintaining a basal cell identity, and blocking it could improve treatment with existing therapies.

## Contribution

EZH2 is shown to drive HER2+ tumor progression by repressing luminal differentiation and promoting basal identity, with implications for combination therapies.

## Key findings

- Genetic ablation of Ezh2 inhibits tumor initiation, progression, and metastasis in HER2-driven mouse models.
- EZH2 inhibition reactivates luminal differentiation and increases ER expression, sensitizing HER2+ cells to Tamoxifen.
- EZH2 inhibitors synergize with Tamoxifen to reduce proliferation of HER2+ breast cancer cell lines in vitro.

## Abstract

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.

This study establishes a role for EZH2 in HER2+ breast cancer progression through driving basal identity. Loss or inhibition of EZH2 reactivates a luminal cellular differentiation program, sensitizing HER2+ breast cancer cells to ER-targeted therapy.

Genetic ablation of Ezh2 in a HER2-driven mouse model inhibits tumor initiation, progression and lung metastasis.Ezh2 loss in HER2+ tumors result in loss of basal/EMT cells and acquisition of a luminal phenotype.ChIP analyses reveal Esr1 as a direct target of PRC2-mediated H3K27me3 repression.EZH2 inhibitors and Tamoxifen synergistically reduce proliferation of human HER2+ breast cancer cell lines in vitro.

Genetic ablation of Ezh2 in a HER2-driven mouse model inhibits tumor initiation, progression and lung metastasis.

Ezh2 loss in HER2+ tumors result in loss of basal/EMT cells and acquisition of a luminal phenotype.

ChIP analyses reveal Esr1 as a direct target of PRC2-mediated H3K27me3 repression.

EZH2 inhibitors and Tamoxifen synergistically reduce proliferation of human HER2+ breast cancer cell lines in vitro.

This study establishes a role for EZH2 in HER2+ breast cancer progression through driving basal identity. Loss or inhibition of EZH2 reactivates a luminal cellular differentiation program, sensitizing HER2+ breast cancer cells to ER-targeted therapy.