Why Tamoxifen Increases Uterine Cancer Risk

Tamoxifen has long stood as a standard treatment for estrogen receptor‑positive breast cancer, helping reduce recurrence and improve survival. Yet clinicians have recognized one troubling paradox: patients using tamoxifen face a higher risk of developing uterine cancer, and until now the underlying mechanism remained elusive.

According to a new study published in Nature Genetics, tamoxifen appears to activate the PI3K signaling pathway in uterine tissue, providing a direct molecular explanation for the increased cancer risk. Researchers at the Berlin Institute of Health in der Charité mapped how tamoxifen induces PI3K activation, thereby bypassing the mutations that typically drive sporadic uterine cancer. The discovery sheds light on why tamoxifen, while highly effective in breast cancer therapy, can unintentionally promote secondary tumors in the uterus.

This molecular insight provides a clearer understanding of tamoxifen’s dual nature. While the drug blocks estrogen in breast tissue, benefiting patients, it can mimic estrogen’s effects in the uterus and trigger harmful cellular activity. According to co-corresponding author Rinath Jeselsohn, MD, using a PI3K inhibitor like alpelisib alongside tamoxifen significantly reduced PI3K signaling, cell proliferation, and pathway activation in lab models. This finding points to the possibility of reducing uterine cancer risk without compromising breast cancer treatment.

The broader context confirms longstanding data. Uterine cancer risk among tamoxifen users is not negligible. Clinical trials and observational studies have shown a twofold to sevenfold increase in incidence within five years of treatment, with longer durations further escalating risk.

Tamoxifen remains a key therapy, especially for premenopausal women, and its life‑saving benefits are well documented. Yet according to thousands of patients and decades of research, balancing treatment efficacy with long-term safety is critical. This new study provides a clear path forward, suggesting tailored combination therapies that could preserve tamoxifen’s benefits while mitigating unintended risks.