与癌症相关的选择性剪接（AS）事件会产生与癌症相关的转录物，这些转录物参与不受控制的细胞增殖和耐药性。然而，与乳腺癌他莫昔芬 (TAM) 耐药相关的关键 AS 变异仍然难以捉摸。在当前的研究中，我们调查了接受 TAM 治疗的九对原发性和复发性乳腺肿瘤患者的 AS 事件情况。我们没有揭示 ALDOA mRNA 5'非翻译区 (5'UTR) 中外显子 7.2 的包含与 TAM 耐药性之间的显着关联。从机制上讲，ALDOA 外显子 7.2 的包含增强了转录本的翻译效率，导致 ALDOA 蛋白表达增加、mTOR 通路活性增加，并促进乳腺癌细胞对 TAM 耐药。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，ALDOA 外显子 7.2 内含物或 MSI1 表达升高与接受内分泌治疗的患者的不良预后相关。值得注意的是，ALDOA 抑制剂 Aldometanib 的治疗可在体外和体内有效抑制 TAM 耐药乳腺癌细胞的生长。本研究揭示了 ALDOA 中的 AS 事件在 MSI1 的调节下在驱动乳腺癌 TAM 耐药性中的关键作用。因此，这项研究提供了一种有前途的针对 ALDOA 来对抗 TAM 耐药性的治疗途径。© 2024。作者，获得 Springer Nature Limited 的独家许可。

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.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.