2. Academic Validation
  3. Alternative splicing of ALDOA confers tamoxifen resistance in breast cancer

Alternative splicing of ALDOA confers tamoxifen resistance in breast cancer

  • Oncogene. 2024 Sep;43(39):2901-2913. doi: 10.1038/s41388-024-03134-w.
Shiyi Yu # 1 2,  Rui Wu # 3,  Yue Si 1 2,  Zhehao Fan 1 2,  Ying Wang 4,  Chang Yao 5,  Rongmao Sun 4,  Yaji Xue 1 2,  Yongli Chen 1 2,  Zheng Wang 6,  Shuangshuang Dong 7,  Ning Wang 1 2,  Xinyue Ling 1 2,  Zhengyan Liang 8,  Caili Bi 1 2,  Yi Yang 9 10,  Weibing Dong 11,  Haibo Sun 12 13 14
Affiliations

Affiliations

  • 1 Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China.
  • 2 Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, China.
  • 3 School of Life Science, Liaoning Normal University, Dalian, China.
  • 4 Department of Thyroid and Breast Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China.
  • 5 The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
  • 6 Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China.
  • 7 Department of Pathology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University/Clinical Medical College, Yangzhou University, Yangzhou, China.
  • 8 School of Basic Medical Science, Guangdong Medical University, Dongguan, China.
  • 9 Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China. yiyang187@foxmail.com.
  • 10 Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, China. yiyang187@foxmail.com.
  • 11 School of Life Science, Liaoning Normal University, Dalian, China. weibing.dong@lnnu.edu.cn.
  • 12 Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China. Sun@yzu.edu.cn.
  • 13 Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, China. Sun@yzu.edu.cn.
  • 14 Haian Hospital of Traditional Chinese Medicine, Haian, China. Sun@yzu.edu.cn.
  • # Contributed equally.
PMID: 39164523 DOI: 10.1038/s41388-024-03134-w
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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