An international research team has identified a previously unknown mechanism by which the breast cancer drug tamoxifen can increase the risk of secondary tumors in the uterus.

The study shows that tamoxifen directly activates a key cellular signaling pathway (known as PI3K) a central driver in the development of sporadic uterine cancers, thereby challenging previously accepted models of therapy-related cancer development.

Since its introduction in the 1970s, tamoxifen has significantly improved survival rates for millions of patients with estrogen receptor–positive breast cancer. However, alongside its life-saving benefits, tamoxifen has also been linked—though rarely—to an elevated risk of uterine cancer. Until now, the precise molecular cause of this effect has remained unclear.

The new findings, published in Nature Genetics, reveal the mechanism: in tamoxifen-associated uterine carcinomas, mutations in the cancer-related gene PIK3CA—which are very common in spontaneously arising uterine tumors and lead to the activation of the PI3K signaling pathway—occur significantly less frequently. Instead, tamoxifen itself takes on the role of a signal activator of the PI3K pathway, making such mutations unnecessary.

The research brought together Prof. Kirsten Kübler from the Berlin Institute of Health at Charité (BIH) with colleagues from Broad Institute of MIT and Harvard, Mass General Brigham and Dana-Farber Cancer 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, 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.”

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.