The findings challenge long-standing assumptions about therapy-related cancers. They also highlight how drug actions can substitute for genetic changes in tumor development.
An international team of researchers, including Prof. Kirsten Kübler from the Berlin Institute of Health at Charité (BIH) and collaborators at the Broad Institute of MIT and Harvard, Mass General Brigham, and the Dana-Farber Cancer Institute, has uncovered a previously unrecognized mechanism through which the breast cancer medication tamoxifen can raise the risk of secondary tumors in the uterus.
The study demonstrates that tamoxifen directly stimulates a major cellular signaling pathway (PI3K), a critical driver in the formation of spontaneous uterine cancers, thereby challenging earlier models of how therapy-related cancers develop.
Life-saving drug with rare complications
Since the 1970s, tamoxifen has played a central role in improving survival for millions of patients with estrogen receptor–positive breast cancer. Despite its proven effectiveness, the drug has also been associated, albeit infrequently, with a higher likelihood of uterine cancer. The specific molecular reason for this link, however, has until now remained unresolved.
The research provides clarity: in uterine cancers associated with tamoxifen, mutations in the cancer-related gene PIK3CA — which are usually common in spontaneously occurring uterine tumors and trigger activation of the PI3K pathway — appear much less often. Instead, tamoxifen itself directly activates the PI3K pathway, eliminating the need for these mutations to drive tumor development.
“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, research group leader 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.”
Towards Improved Therapeutic Safety
While the overall risk of developing uterine cancer during tamoxifen therapy remains very low — and the benefits of the drug far outweigh the risks — the findings open up new opportunities for further improving treatment safety. In addition to offering a biological explanation for this long-standing medical puzzle, the discovery lays the groundwork for personalized prevention and intervention strategies.
In future projects, the researchers plan to investigate whether similar mechanisms may also play a role in the side effects of other medications.
Reference: “Tamoxifen induces PI3K activation in uterine cancer” by Kirsten Kübler, Agostina Nardone, Shankara Anand, Daniel Gurevich, Jianjiong Gao, Marjolein Droog, Francisco Hermida-Prado, Tara Akhshi, Ariel Feiglin, Avery S. Feit, Gabriella Cohen Feit, Gwen Dackus, Matthew Pun, Yanan Kuang, Justin Cha, Mendy Miller, Sebastian Gregoricchio, Mirthe Lanfermeijer, Sten Cornelissen, William J. Gibson, Cloud P. Paweletz, Eliezer M. Van Allen, Flora E. van Leeuwen, Petra M. Nederlof, Quang-Dé Nguyen, Marian J. E. Mourits, Milan Radovich, Ignaty Leshchiner, Chip Stewart, Ursula A. Matulonis, Wilbert Zwart, Yosef E. Maruvka, Gad Getz and Rinath Jeselsohn, 22 August 2025, Nature Genetics.
DOI: 10.1038/s41588-025-02308-w
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