Alternative splicing of ALDOA confers tamoxifen resistance in breast cancer

IF 6.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Oncogene Pub Date : 2024-08-20 DOI:10.1038/s41388-024-03134-w

Shiyi Yu, Rui Wu, Yue Si, Zhehao Fan, Ying Wang, Chang Yao, Rongmao Sun, Yaji Xue, Yongli Chen, Zheng Wang, Shuangshuang Dong, Ning Wang, Xinyue Ling, Zhengyan Liang, Caili Bi, Yi Yang, Weibing Dong, Haibo Sun

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Abstract

The cancer-associated alternative splicing (AS) events generate cancer-related transcripts which are involved in uncontrolled cell proliferation and drug resistance. However, the key AS variants implicated in tamoxifen (TAM) resistance in breast cancer remain elusive. In the current study, we investigated the landscape of AS events in nine pairs of primary and relapse breast tumors from patients receiving TAM-based therapy. We unrevealed a notable association between the inclusion of exon 7.2 in the 5’untranslated region (5’UTR) of ALDOA mRNA and TAM resistance. Mechanistically, the inclusion of ALDOA exon 7.2 enhances the translation efficiency of the transcript, resulting in increased ALDOA protein expression, mTOR pathway activity, and the promotion of TAM resistance in breast cancer cells. Moreover, the inclusion of exon 7.2 in ALDOA mRNA is mediated by MSI1 via direct interaction. In addition, elevated inclusion of ALDOA exon 7.2 or expression of MSI1 is associated with an unfavorable prognosis in patients undergoing endocrine therapy. Notably, treatment with Aldometanib, an ALDOA inhibitor, effectively restrains the growth of TAM-resistant breast cancer cells in vitro and in vivo. The present study unveils the pivotal role of an AS event in ALDOA, under the regulation of MSI1, in driving TAM resistance in breast cancer. Therefore, this study provides a promising therapeutic avenue targeting ALDOA to combat TAM resistance.

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ALDOA 的交替剪接使乳腺癌产生他莫昔芬抗药性。

与癌症相关的替代剪接（AS）事件会产生与癌症相关的转录本，这些转录本参与了不受控制的细胞增殖和耐药性。然而，与乳腺癌中他莫昔芬（TAM）耐药性有关的关键AS变体仍然难以捉摸。在本研究中，我们调查了接受他莫昔芬治疗的九对原发性和复发性乳腺肿瘤中的AS事件。我们发现，ALDOA mRNA的5'非翻译区（5'UTR）中包含7.2号外显子与TAM耐药之间存在明显的关联。从机理上讲，ALDOA 7.2 号外显子的加入提高了转录本的翻译效率，从而增加了 ALDOA 蛋白的表达、mTOR 通路的活性，并促进了乳腺癌细胞对 TAM 的耐药性。此外，ALDOA mRNA 中外显子 7.2 的包含是由 MSI1 通过直接相互作用介导的。此外，在接受内分泌治疗的患者中，ALDOA 7.2外显子的包含或MSI1的表达升高与预后不良有关。值得注意的是，Aldometanib 是一种 ALDOA 抑制剂，它能有效抑制 TAM 抗性乳腺癌细胞在体外和体内的生长。本研究揭示了在 MSI1 的调控下，ALDOA 中的 AS 事件在驱动乳腺癌 TAM 抗性中的关键作用。因此，本研究为靶向 ALDOA 对抗 TAM 抗性提供了一条前景广阔的治疗途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.