Tamoxifen's Unexpected Effect on Uterine Cancer Risk

A global research team has uncovered a previously unknown mechanism through which the breast cancer medication tamoxifen can elevate the risk of uterine tumors.

The study demonstrates that tamoxifen directly activates the PI3K cellular signaling pathway—a central driver in sporadic uterine cancers—challenging previous assumptions about therapy-related cancer development.

Since its inception in the 1970s, tamoxifen has greatly enhanced survival rates for millions of patients with estrogen receptor-positive breast cancer. However, despite its life-saving potential, it is occasionally linked to an increased risk of uterine cancer. Until now, the precise molecular cause behind this effect remained unclear.

The new findings published in Nature Genetics, reveal the mechanism: in tamoxifen-associated uterine carcinomas, mutations in the PIK3CA gene—a common occurrence in spontaneous uterine tumors—are fewer compared to non-tamoxifen cases. Instead, tamoxifen itself acts as a signal activator of the PI3K pathway, rendering these genetic changes unnecessary.

The study involved collaboration between Prof. Kirsten Kübler from the Berlin Institute of Health at Charité (BIH), alongside colleagues from Broad Institute of MIT and Harvard, Mass General Brigham, and Dana-Farber Cancer Institute.

"Our results demonstrate for the first time that a drug can activate a pro-tumor signaling pathway, offering a molecular explanation for how an effective cancer treatment like tamoxifen could paradoxically promote tumor development in another tissue," explains Prof. Kirsten Kübler, research group leader at BIH.

"By directly stimulating the PI3K signaling pathway, tamoxifen bypasses the need for genetic mutations that typically drive uterine cancers."

While the overall risk of developing uterine cancer during tamoxifen therapy remains low—with its benefits greatly outweighing the risks—the findings offer new insights into enhancing treatment safety. Beyond providing a biological explanation for this long-standing medical riddle, the discovery paves the way for personalized prevention and intervention strategies.

Future research aims to determine if similar mechanisms are at play in side effects of other medications.