Tamoxifen is an essential drug in breast cancer therapy. Unlike prevailing models of therapy-related tumorigenesis, tamoxifen acts by directly activating the PI3K pathway, bypassing the need for mutations in one of the most common driver genes in sporadic uterine cancer. These findings open avenues for investigating similar mechanisms in other drugs.
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References
Jordan, V. C. Tamoxifen: a most unlikely pioneering medicine. Nat. Rev. Drug Discov. 2, 205–213 (2003). A review article that presents the discovery, development and clinical impact of tamoxifen.
Fisher, B. et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J. Natl Cancer Inst. 86, 527–537 (1994). This paper reports an increased risk of uterine cancer in patients treated with tamoxifen.
Shang, Y. & Brown, M. Molecular determinants for the tissue specificity of SERMs. Science 295, 2465–2468 (2002). This paper reports the tissue-specific effects of tamoxifen in breast and endometrial cells.
Moore, L. et al. The mutational landscape of normal human endometrial epithelium. Nature 580, 640–646 (2020). This paper reports that normal endometrial tissue harbors clonal expansions with somatic mutations.
Cuzick, J. et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol. 16, 67–75 (2015). This paper reports that tamoxifen provides sustained protection, thereby improving its benefit-to-harm ratio.
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This is a summary of: Kübler, K. et al. Tamoxifen induces PI3K activation in uterine cancer. Nat. Genet. https://doi.org/10.1038/s41588-025-02308-w (2025).
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Mystery of tamoxifen-associated uterine cancer uncovered. Nat Genet 57, 2084–2085 (2025). https://doi.org/10.1038/s41588-025-02316-w
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DOI: https://doi.org/10.1038/s41588-025-02316-w
