Cancer-associated fibroblast promotes tamoxifen resistance in estrogen receptor positive breast cancer via exosomal LncRNA PRKCQ-AS1/miR-200a-3p/MKP1 axis-mediated apoptosis suppression

作者：Chenghui Wu, Xi Sun, Yujie Lu, Haoyu Wang, Zhengyuan Yu, Zheng Wang, Renhong Huang, Yihua Jin, Xing Chen, Xing Chen, Haixia Xie, Yu Zong, Kunwei Shen, Min Jiang, Yujie Tang, Xiaosong Chen, Xiaosong Chen · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2025 · DOI：10.1186/s13046-025-03529-x · 被引用次数：5 · 研究领域：Cancer-related molecular mechanisms research、MicroRNA in disease regulation、Circular RNAs in diseases

BACKGROUND: Tamoxifen resistance remains a significant challenge in the endocrine therapy of estrogen receptor-positive (ER+) breast cancer. Cancer-associated fibroblasts (CAFs) facilitate therapeutic resistance through exosome secretion, yet the role of CAF-derived long non-coding RNAs (lncRNAs) in tamoxifen resistance remains underexplored. This study investigates the mechanism by which CAF-secreted exosomal lncRNA modulates tamoxifen resistance in ER + breast cancer. METHODS: CAFs from ER + breast cancer patients and normal fibroblasts (NFs) from healthy control were isolated and cultured ex vivo. Exosomes were extracted from the supernatant of cultured cells using ultracentrifugation. RNA sequencing identified PRKCQ-AS1 as a candidate lncRNA, validated in tamoxifen-sensitive and resistant tumors. Functional assays (qPCR, RNA-seq, dual-luciferase reporter, and in vivo xenografts) elucidated the role of PRKCQ-AS1/miR-200a-3p/MKP1 axis in tamoxifen resistance. Prognostic correlations were assessed in clinical cohorts (n = 471) and TCGA/GEO datasets. RESULTS: LncRNA PRKCQ-AS1 was markedly upregulated in tamoxifen-resistant tumor samples and was associated with poor prognosis in tamoxifen-treated ER + breast cancer patients but not in those treated with aromatase inhibitors. Exosomal PRKCQ-AS1 derived from CAFs transferred to ER + breast cancer cells, suppressing tamoxifen-induced apoptosis via MKP1 upregulation. Mechanistically, PRKCQ-AS1 acted as a molecular sponge for miR-2...