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雌激素诱导的FXR1通过BCL2和GPX4促进乳腺癌的内分泌抵抗和骨转移。

Estrogen-induced FXR1 promotes endocrine resistance and bone metastasis in breast cancer via BCL2 and GPX4.

作者信息

Shang Yinzhong, Cao Tingfang, Ma Xin, Huang Le, Wu Mingming, Xu Junchao, Wang Jiarui, Wang Hao, Wu Sheng, Pandey Vijay, Wu Zhengsheng, Zhang Weijie, Lobie Peter E, Han Xinghua, Zhu Tao

机构信息

Department of Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, National Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei, China.

Shenzhen Bay Laboratory, Institute of Biomedical Health Technology and Engineering, Shenzhen, China.

出版信息

Front Cell Dev Biol. 2025 Mar 24;13:1563353. doi: 10.3389/fcell.2025.1563353. eCollection 2025.

DOI:10.3389/fcell.2025.1563353
PMID:40196843
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11973456/
Abstract

Estrogen signaling dysregulation plays a critical role in the development of anti-estrogen resistance and bone metastasis of ER+ mammary carcinoma. Using quantitative proteomic screening, we identified FXR1 as an estrogen-regulated RNA-binding protein associated with anti-estrogen resistance. Mechanistically, estrogen and IGF1 facilitate FXR1 protein translation via the PI3K/AKT/mTOR/EIF4E pathway. FXR1 enhances cellular resistance to apoptosis and ferroptosis by facilitating the maturation of BCL2 pre-mRNA and stabilizing GPX4 mRNA, respectively. Anti-estrogen resistant cells exhibit elevated FXR1 expression, and FXR1 depletion restores their sensitivity to tamoxifen. Moreover, combining FXR1 depletion with a ferroptosis inducer induces synergistic lethal in anti-estrogen resistant cells. Finally, we provide proof-of-concept evidence supporting FXR1 antagonism as a potential treatment for bone metastases in ER+ breast cancer. Our findings highlight FXR1 as a promising therapeutic target to improve existing therapeutic regimes for ER+ breast cancer patients.

摘要

雌激素信号失调在雌激素受体阳性（ER+）乳腺癌的抗雌激素耐药性及骨转移发展过程中起关键作用。通过定量蛋白质组学筛选，我们鉴定出FXR1是一种与抗雌激素耐药性相关的雌激素调节RNA结合蛋白。从机制上讲，雌激素和胰岛素样生长因子1（IGF1）通过PI3K/AKT/mTOR/EIF4E途径促进FXR1蛋白翻译。FXR1分别通过促进BCL2前体mRNA的成熟和稳定谷胱甘肽过氧化物酶4（GPX4）mRNA来增强细胞对凋亡和铁死亡的抗性。抗雌激素耐药细胞表现出FXR1表达升高，而FXR1的缺失可恢复它们对他莫昔芬的敏感性。此外，将FXR1缺失与铁死亡诱导剂联合使用可在抗雌激素耐药细胞中诱导协同致死作用。最后，我们提供了概念验证证据，支持将FXR1拮抗作用作为ER+乳腺癌骨转移的一种潜在治疗方法。我们的研究结果突出了FXR1作为一个有前景的治疗靶点，可改善ER+乳腺癌患者现有的治疗方案。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a04c/11973456/78570f62bbfe/fcell-13-1563353-g007.jpg
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本文引用的文献

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J Hematol Oncol. 2024 Jun 6;17(1):41. doi: 10.1186/s13045-024-01564-3.
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PRMT5-mediated arginine methylation of FXR1 is essential for RNA binding in cancer cells.PRMT5 介导的 FXR1 精氨酸甲基化对于癌细胞中的 RNA 结合至关重要。
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Recent trends and advances in novel formulations as an armament in Bcl-2/Bax targeted breast cancer.新型制剂在 Bcl-2/Bax 靶向乳腺癌中的最新趋势和进展。
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Estrogen Receptor Signaling in Breast Cancer.乳腺癌中的雌激素受体信号传导
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Global impact of somatic structural variation on the cancer proteome.体细胞结构变异对癌症蛋白质组的全球影响。
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Molecular Mechanisms of Anti-Estrogen Therapy Resistance and Novel Targeted Therapies.抗雌激素治疗耐药性的分子机制及新型靶向治疗
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Proteogenomic characterization of 2002 human cancers reveals pan-cancer molecular subtypes and associated pathways.2002 例人类癌症的蛋白质基因组学特征分析揭示了泛癌分子亚型及相关途径。
Nat Commun. 2022 May 13;13(1):2669. doi: 10.1038/s41467-022-30342-3.
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Cooperative interaction between ERα and the EMT-inducer ZEB1 reprograms breast cancer cells for bone metastasis.雌激素受体α（ERα）与 EMT 诱导因子 ZEB1 的协同互作对乳腺癌细胞向骨转移进行重编程。
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The Signaling Pathways Associated With Breast Cancer Bone Metastasis.与乳腺癌骨转移相关的信号通路
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