Authors: Rui Zhang, Wen-Jing Jiang, Shuai Zhao, Li-Juan Kang, Qing-Shan Wang, Yu-Mei Feng
Published: 2025-04-21
DOI: 10.1158/1538-7445.am2025-1312
Source: Full article
Estrogen receptor-positive (ER+) breast cancer accounts for 80% breast cancer cases. The estrogen-ERα signaling pathway plays a pivotal role in driving the progression of ER+ breast cancer cells. Thus, endocrine therapy targeting the estrogen-ERα signaling pathway is a predominant treatment for ER+ breast cancer. Most patients with ER+ breast cancer require long-term treatment with endocrine agents. Although endocrine therapy effectively improves the survival of patients with ER+ breast cancer, bone metastasis frequently occurs in patients receiving long-term endocrine therapy due to acquired resistance. Elucidating the molecular mechanisms underlying endocrine-resistance and developing effective strategies to reverse resistance or treat resistant tumors are crucial unresolved issues. Enhancer reprogramming-mediated lineage-specific transcriptional rewiring systemically regulates the transdifferentiation and plasticity of cancer cells. Enhancers are DNA regulatory elements composed of clusters of transcription factor (TF) binding sites. Enhancer-bound TFs recruit chromatin-modifying enzymes to establish unique histone modifications in enhancer regions, subsequently recruiting cofactors to facilitate or repress the transcription of specific target genes by reorganizing chromatin architecture and altering DNA accessibility. Our previous studies found that forkhead box F2 (FOXF2), a mesenchymal TF, is barely expressed in ER+/luminal breast cancer (LumBC) cells but is commonly expressed in triple-negative breast cancer (TNBC)/basal-like breast cancer (BLBC) cells with mesenchymal characteristics. In the present study, we found that ERα represses FOXF2 transcription in ER+ breast cancer through H3K27me3 modification, therefore endocrine therapy triggers FOXF2 transcription by loss of H3K27me3. FOXF2 transactivation orchestrates endocrine-resistance and bone metastasis. Mechanically, FOXF2 globally activates enhancers of genes involved in epithelial-mesenchymal transition (EMT)/epithelial-osteogenic transition (EOT), as well as super-enhancers of NCOA3 (a coactivator of FOXF2) and SP1 (an upstream trans-activator of FOXF2) by recruiting SWI/SNF complex that mediates the reorganization of chromatin architecture. Targeting BRD4, an essential transcriptional coactivator of FOXF2, significantly inhibits FOXF2-orchestrated endocrine-resistance and bone metastases. Our findings uncover a mechanism underlying endocrine-resistance and provide a promising strategy for managing endocrine-resistant breast cancer.