Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China.
Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, China.
Oncogene. 2024 Sep;43(39):2901-2913. doi: 10.1038/s41388-024-03134-w. Epub 2024 Aug 20.
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.
癌症相关的可变剪接（AS）事件产生与癌症相关的转录本，这些转录本参与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）耐药相关的关键 AS 变体仍难以捉摸。在本研究中，我们研究了 9 对接受 TAM 为基础的治疗的原发性和复发性乳腺癌肿瘤中的 AS 事件的情况。我们揭示了在 ALDOA mRNA 的 5'非翻译区（5'UTR）中包含外显子 7.2 与 TAM 耐药之间存在显著相关性。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 通路活性增强，并促进乳腺癌细胞中的 TAM 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，ALDOA 外显子 7.2 的包含增加或 MSI1 的表达与接受内分泌治疗的患者预后不良有关。值得注意的是，用 ALDOA 抑制剂 Aldometanib 治疗可有效抑制体外和体内 TAM 耐药性乳腺癌细胞的生长。本研究揭示了在 MSI1 调节下，ALDOA 中的一个 AS 事件在驱动乳腺癌中 TAM 耐药性方面的关键作用。因此，该研究为靶向 ALDOA 以克服 TAM 耐药性提供了一个有前途的治疗途径。
