Abstract PS1-12-03: Aberrant exon skipping of ALDOA confers tamoxifen resistance in breast cancer

Abstract Breast cancer is the most commonly diagnosed malignancy worldwide, with over 2.6 million new cases reported annually. A substantial proportion of these cases are estrogen receptor-positive (ER+), representing the most prevalent molecular subtype. Standard treatment for ER+ breast cancer typically includes adjuvant endocrine therapy with tamoxifen (TAM), which functions by antagonizing estrogen receptor signaling to reduce the risk of disease recurrence following surgery. Despite its clinical efficacy, more than 20% of patients experience either primary or acquired resistance to TAM, ultimately contributing to treatment failure and increased mortality. Cancer-associated alternative splicing (AS) events give rise to aberrant transcript variants that contribute to uncontrolled cell proliferation and therapeutic resistance. Despite growing evidence linking AS to tumor progression, the specific splicing variants involved in TAM resistance in breast cancer remain largely undefined. In this study, we profiled the landscape of AS events in nine pairs of matched primary and relapsed breast tumors from patients treated with TAM-based therapy. Through integrative experimental validations including Ribo-qPCR, RNA pull-down, mass spectrometry, and dual-luciferase reporter assays, we identified a key ALDOA splice variant associated with TAM resistance. Specifically, 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. 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. In conclusion, we provides a promising therapeutic avenue targeting ALDOA to combat TAM resistance. Citation Format: Y. Duan, S. Yu, R. Sang, S. Zhang, Y. Yang, C. Bi, H. Sun. Aberrant exon skipping of ALDOA confers tamoxifen resistance in breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-12-03.