Schematic illustration depicting (1) PIK3CA mutations in TA-UC and de novo UC (prime two left subpanels; bars signify mutation frequencies; error bars mirror s.d. from the β-distribution), (2) the in vivo mouse mannequin (prime proper) with cell morphological modifications from regular atrophic (no tamoxifen (Tam)) and regular proliferative (+E2) to elevated variety of ducts and cell hypertrophy (with tamoxifen) and normalized variety of ducts and cell size (with tamoxifen and PI3K inhibitor), (3) the mannequin of PI3K signaling induced by tamoxifen (center proper) and (4) the mannequin of UC evolution for de novo UC and TA-UC (backside). Credit score: Nature Genetics (2025). DOI: 10.1038/s41588-025-02308-w
A world analysis workforce has recognized a beforehand unknown mechanism by which the breast most cancers drug tamoxifen can improve the chance of secondary tumors within the uterus.
The examine exhibits that tamoxifen straight prompts a key mobile signaling pathway (often known as PI3K) a central driver within the improvement of sporadic uterine cancers, thereby difficult beforehand accepted fashions of therapy-related most cancers improvement.
Since its introduction within the Seventies, tamoxifen has considerably improved survival charges for thousands and thousands of sufferers with estrogen receptor–optimistic breast most cancers. Nonetheless, alongside its life-saving advantages, tamoxifen has additionally been linked—although not often—to an elevated danger of uterine most cancers. Till now, the exact molecular reason for this impact has remained unclear.
The brand new findings, printed in Nature Genetics, reveal the mechanism: in tamoxifen-associated uterine carcinomas, mutations within the cancer-related gene PIK3CA—that are quite common in spontaneously arising uterine tumors and result in the activation of the PI3K signaling pathway—happen considerably much less often. As an alternative, tamoxifen itself takes on the function of a sign activator of the PI3K pathway, making such mutations pointless.
The analysis introduced collectively Prof. Kirsten Kübler from the Berlin Institute of Well being at Charité (BIH) with colleagues from Broad Institute of MIT and Harvard, Mass Basic Brigham and Dana-Farber Most cancers Institute.
“Our results show for the first time that the activation of a pro-tumor signaling pathway by a drug is possible and provides a molecular-level explanation for how a highly successful cancer drug can paradoxically promote tumor development in another tissue,” explains Prof. Kirsten Kübler, analysis group chief at BIH.
“Tamoxifen bypasses the need for genetic mutations in the PI3K signaling pathway, one of the key drivers of uterine cancer, by directly providing the stimulus for tumor formation.”
Whereas the general danger of growing uterine most cancers throughout tamoxifen remedy stays very low—and the advantages of the drug far outweigh the dangers—the findings open up new alternatives for additional bettering remedy security. Along with providing a organic clarification for this long-standing medical puzzle, the invention lays the groundwork for customized prevention and intervention methods.
In future initiatives, the researchers plan to analyze whether or not related mechanisms might also play a task within the negative effects of different drugs.
Extra data:
Kirsten Kübler et al, Tamoxifen induces PI3K activation in uterine most cancers, Nature Genetics (2025). DOI: 10.1038/s41588-025-02308-w
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Berlin Institute of Well being in der Charité
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Breast most cancers drug negative effects: Research reveals how tamoxifen raises danger of secondary tumors in uterus (2025, August 22)
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