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Alternative splicing of ALDOA confers tamoxifen resistance in breast cancer

Shiyi Yu1,2, Rui Wu3, Yue Si1,2

  • 1Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China.

Oncogene
|August 20, 2024
PubMed

Insights

Alternative splicing of ALDOA exon 7.2 drives tamoxifen resistance in breast cancer by increasing protein translation. Targeting ALDOA offers a new strategy against drug-resistant cancers.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genomics

Background:

  • Alternative splicing (AS) generates transcripts linked to cancer progression, including uncontrolled proliferation and drug resistance.
  • Key AS variants driving tamoxifen (TAM) resistance in breast cancer are not fully understood.
  • Investigating AS events in TAM-treated breast cancer patients is crucial for identifying resistance mechanisms.

Purpose of the Study:

  • To identify critical alternative splicing events associated with tamoxifen resistance in breast cancer.
  • To elucidate the molecular mechanisms by which specific AS variants contribute to TAM resistance.
  • To explore potential therapeutic strategies targeting identified AS events or related proteins.

Main Methods:

  • Analysis of alternative splicing landscapes in primary and relapse breast tumors from patients on TAM therapy.
  • Investigating the functional impact of ALDOA exon 7.2 inclusion on translation efficiency and protein expression.
  • Assessing the role of MSI1 in mediating ALDOA exon 7.2 inclusion.
  • Evaluating the efficacy of an ALDOA inhibitor (Aldometanib) in preclinical models of TAM-resistant breast cancer.

Main Results:

  • A significant association was found between ALDOA exon 7.2 inclusion in the 5'UTR and TAM resistance.
  • ALDOA exon 7.2 inclusion enhances translation efficiency, leading to increased ALDOA protein, mTOR pathway activation, and TAM resistance.
  • MSI1 was identified as a key regulator of ALDOA exon 7.2 inclusion through direct interaction.
  • Elevated ALDOA exon 7.2 inclusion or MSI1 expression correlated with poor prognosis in patients receiving endocrine therapy.
  • Aldometanib treatment inhibited the growth of TAM-resistant breast cancer cells in vitro and in vivo.

Conclusions:

  • Alternative splicing of ALDOA exon 7.2, regulated by MSI1, plays a critical role in promoting tamoxifen resistance in breast cancer.
  • Targeting ALDOA presents a promising therapeutic strategy to overcome tamoxifen resistance.
  • This study provides novel insights into the molecular basis of endocrine therapy resistance in breast cancer.

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