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Background <p>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.</p> Methods <p>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 (<i>n</i> = 471) and TCGA/GEO datasets.</p> Results <p>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-200a-3p, relieving miR-200a-3p-mediated repression of MKP1. Elevated MKP1 inactivated the MAPK/JNK pathway, attenuating apoptosis. In vivo, PRKCQ-AS1 overexpression accelerated ER + breast tumor growth despite tamoxifen treatment. TGF-β-driven CAF transformation upregulated PAX5, a transcription factor enhancing PRKCQ-AS1 expression.</p> Conclusions <p>This study identifies CAF-derived exosomal LncRNA PRKCQ-AS1 as a key mediator of tamoxifen resistance via the miR-200a-3p/MKP1 axis. Targeting this pathway may offer novel therapeutic strategies to overcome endocrine resistance in ER + breast cancer.</p>

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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

  • 期刊论文

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  • 发表日期：

    2025年9月30日

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  • Chenghui Wu,
  • Xi Sun,
  • Yujie Lu,
  • Haoyu Wang,
  • Zhengyuan Yu,
  • Zheng Wang,
  • Renhong Huang,
  • Yihua Jin,
  • Xing Chen,
  • Haixia Xie,
  • Yu Zong,
  • Kunwei Shen,
  • Min Jiang,
  • Yujie Tang,
  • Xiaosong Chen

摘要

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-200a-3p, relieving miR-200a-3p-mediated repression of MKP1. Elevated MKP1 inactivated the MAPK/JNK pathway, attenuating apoptosis. In vivo, PRKCQ-AS1 overexpression accelerated ER + breast tumor growth despite tamoxifen treatment. TGF-β-driven CAF transformation upregulated PAX5, a transcription factor enhancing PRKCQ-AS1 expression.

Conclusions

This study identifies CAF-derived exosomal LncRNA PRKCQ-AS1 as a key mediator of tamoxifen resistance via the miR-200a-3p/MKP1 axis. Targeting this pathway may offer novel therapeutic strategies to overcome endocrine resistance in ER + breast cancer.