Tamoxifen & Uterine Cancer Risk: A Potential Preventative Strategy
A new study offers promising insights into a known side effect of a common breast cancer treatment - the increased risk of uterine cancer. While tamoxifen remains a highly effective therapy, research reveals how it can contribute to uterine cancer advancement adn suggests a potential way to mitigate this risk.
Researchers at Mass General Brigham, the Broad Institute, Dana-farber Cancer Institute, and the Berlin Institute of Health (BIH) discovered that tamoxifen activates a cell growth signaling pathway in the uterus, specifically the PI3K-AKT pathway. This activation appears to occur without causing the typical genetic mutations (specifically in the PIK3CA gene) often seen in uterine cancers that develop independently of tamoxifen treatment. Actually, uterine cancers linked to tamoxifen use showed significantly lower rates of these PIK3CA mutations.
the study, published in Nature Genetics, demonstrated in mice that tamoxifen exposure led to increased activity in the PI3K-AKT pathway, driven in part by the growth-promoting hormone IGF1. Crucially, when mice were treated with both tamoxifen and alpelisib – a drug that blocks the PI3K pathway - PI3K-AKT signaling, IGF1 receptor activation, and cell proliferation were significantly reduced.
These findings suggest that blocking the PI3K pathway could offer a preventative measure against tamoxifen-associated uterine cancer.
“Future clinical research can confirm whether combining non-mutant selective PI3K inhibitors with tamoxifen reduces the risk of uterine cancer and ultimately saves lives,” says Dr. Rinath Jeselsohn of Dana-Farber Cancer Institute and the Broad Institute. this research could ultimately change how some breast cancers are treated, improving long-term outcomes for patients.
Source: Kübler, K.,et al. (2025). Tamoxifen induces PI3K activation in uterine cancer. Nature Genetics. doi.org/10.1038/s41588-025-02308-w