Synergistic interplay between PHF8 and HER2 signaling contributes to breast cancer development and drug resistance

HER2 plays a critical role in tumorigenesis and is associated with poor prognosis of HER2-positive breast cancers. Although, anti-HER2 drugs show benefits in breast cancer therapy, de novo or acquired resistance often develop. Epigenetic factors have been increasingly targeted for therapeutic purposes, however, such mechanisms interacting with HER2 signaling are poorly understood. This study reports the synergistic interplay between histone demethylase PHF8 and HER2 signaling, i.e. PHF8 is elevated in HER2-positive breast cancers and is upregulated by HER2; PHF8 plays coactivator roles in regulating HER2 expression and HER2-driven epithelial-to-mesenchymal transition (EMT) markers and cytokines. The HER2-PHF8-IL-6 regulatory axis was proved both in cell lines and in the newly established MMTV-Her2/MMTV-Cre/Phf8flox/flox models, with which the oncogenic function of Phf8 in breast cancer in vivo was revealed for the first time. Furthermore, PHF8-IL-6 axis contributes to the resistance of Trastuzumab in vitro and may play a critical role in the infiltration of T-cells in HER2-driven breast cancers. This study reveals novel epigenetic mechanisms underlying HER2-driven cancer development and anti-HER2 drug resistance.