biostudies-literatureKubler KG.G. is partly supported by the Paul C. Zamecnik Chair in Oncology at the Massachusetts General Hospital Cancer Center.U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research ProgramsU.S. Department of Health & Human Services | NIH | National Cancer InstituteUnited States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP)U.S. Department of DefenseU.S. Department of Defense (United States Department of Defense)NCI NIH HHSKWF Kankerbestrijding2192-2202https://www.ebi.ac.uk/biostudies/studies/S-EPMC12425819biostudies-literatureUnknown57(9)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, Nature geneticsTamoxifen induces PI3K activation in uterine cancer.PMC12425819W81XWH-17-1-0084K08 CA191058P50CA2402435K08CA191058-05P50 CA240243R01 CA237414Lanfermeijer MFeit ASNederlof PMMiller MNardone AHermida-Prado FGibson WJDroog MCha JGetz GLeshchiner IPun MGao JRadovich MZwart WCohen Feit GVan Allen EMStewart CDackus Gvan Leeuwen FEKubler KMourits MJEMatulonis UANguyen QDJeselsohn RMaruvka YEPaweletz CPAnand SKuang YAkhshi TGregoricchio SGurevich DCornelissen SFeiglin AfalseTamoxifen induces PI3K activation in uterine cancer.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, 2025-01-01T00:00:00Z2025 Sep2026-06-03T02:51:29.927Z2026-04-23T03:11:55.534ZS-EPMC124258194084676210.1038/s41588-025-02308-w