FOXF2 expression triggered by endocrine therapy orchestrates therapeutic resistance through reorganization of chromatin architecture in breast cancer

Patients with estrogen receptor-positive (ER+) breast cancer require long-term endocrine therapy. However, endocrine resistance remains a critical issue to be addressed. Herein, we show that ERα repressed FOXF2 transcription in ER+ breast cancer through H3K27me3 modification, therefore endocrine therapy triggered FOXF2 transcription via loss of H3K27me3. FOXF2 transactivation orchestrated endocrine resistance and bone metastasis. Mechanistically, FOXF2 globally activated enhancers of genes involved in epithelial-mesenchymal transition/epithelial-osteogenic transition, as well as super-enhancers of NCOA3 (a coactivator of FOXF2) and SP1 (an upstream transactivator of FOXF2) by recruiting the SWI/SNF complex that mediates the reorganization of chromatin architecture. Forthermore, FOXF2 systematically modulates the reorganization of chromatin architecture and gene expression by recruiting SMARCC1. Therefore, FOXF2 acts as a pioneer factor to orchestrate endocrine resistance through the reorganization of chromatin architecture. Additionally, FOXF2 expression levels in the tumors of ER+ breast cancer predicted response to endocrine therapeutic drugs and outcome of patients. Targeting BRD4, an essential transcriptional coactivator of FOXF2, significantly inhibited FOXF2-orchestrated endocrine-resistance and bone metastasis. Our findings uncover a mechanism underlying endocrine resistance and provide a promising strategy for managing endocrine-resistant breast cancer.