Tamoxifen induces PI3K activation in uterine cancer

作者：Kirsten Kübler, Agostina Nardone, Shankara K. Anand, Daniel Gurevich, Jianjiong Gao, Marjolein Droog, Francisco Hermida‐Prado, Tara Akhshi, Ariel Feiglin, Avery S. Feit, Gabriella Cohen, Gwen M. H. E. Dackus, Matthew J Pun, Yanan Kuang, Justin Cha, Mendy L. Miller, Sebastian Gregoricchio, Mirthe Lanfermeijer, Sten Cornelissen, William J. Gibson, Cloud Peter 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 T. Zwart, Yosef E. Maruvka, Gad A. Getz, Rinath M. Jeselsohn · 发表于：Nature Genetics · 年份：2025 · DOI：10.1038/s41588-025-02308-w · 被引用次数：7 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Estrogen and related hormone effects、Ovarian cancer diagnosis and treatment

Mutagenic processes and clonal selection contribute to the development of therapy-associated secondary neoplasms, a known complication of cancer treatment. The association between tamoxifen therapy and secondary uterine cancers is uncommon but well established; however, the genetic mechanisms underlying tamoxifen-driven tumorigenesis remain unclear. We find that oncogenic PIK3CA mutations, common in spontaneously arising estrogen-associated de novo uterine cancer, are significantly less frequent in tamoxifen-associated tumors. In vivo, tamoxifen-induced estrogen receptor stimulation activates phosphoinositide 3-kinase (PI3K) signaling in normal mouse uterine tissue, potentially eliminating the selective benefit of PI3K-activating mutations in tamoxifen-associated uterine cancer. Together, we present a unique pathway of therapy-associated carcinogenesis in which tamoxifen-induced activation of the PI3K pathway acts as a non-genetic driver event, contributing to the multistep model of uterine carcinogenesis. While this PI3K mechanism is specific to tamoxifen-associated uterine cancer, the concept of treatment-induced signaling events may have broader applicability to other routes of tumorigenesis.