000304084 001__ 304084 000304084 005__ 20250831022503.0 000304084 0247_ $$2doi$$a10.1038/s41588-025-02308-w 000304084 0247_ $$2pmid$$apmid:40846762 000304084 0247_ $$2ISSN$$a1061-4036 000304084 0247_ $$2ISSN$$a1546-1718 000304084 0247_ $$2altmetric$$aaltmetric:180511064 000304084 037__ $$aDKFZ-2025-01752 000304084 041__ $$aEnglish 000304084 082__ $$a570 000304084 1001_ $$00000-0002-0342-5579$$aKübler, Kirsten$$b0 000304084 245__ $$aTamoxifen induces PI3K activation in uterine cancer. 000304084 260__ $$aLondon$$bMacmillan Publishers Limited, part of Springer Nature$$c2025 000304084 3367_ $$2DRIVER$$aarticle 000304084 3367_ $$2DataCite$$aOutput Types/Journal article 000304084 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1756189411_30611 000304084 3367_ $$2BibTeX$$aARTICLE 000304084 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000304084 3367_ $$00$$2EndNote$$aJournal Article 000304084 500__ $$aepub 000304084 520__ $$aMutagenic processes and clonal selection contribute to the development of therapy-associated secondary neoplasms, a known complication of cancer treatment. The association between tamoxifen therapy and secondary uterine cancers is uncommon but well established; however, the genetic mechanisms underlying tamoxifen-driven tumorigenesis remain unclear. We find that oncogenic PIK3CA mutations, common in spontaneously arising estrogen-associated de novo uterine cancer, are significantly less frequent in tamoxifen-associated tumors. In vivo, tamoxifen-induced estrogen receptor stimulation activates phosphoinositide 3-kinase (PI3K) signaling in normal mouse uterine tissue, potentially eliminating the selective benefit of PI3K-activating mutations in tamoxifen-associated uterine cancer. Together, we present a unique pathway of therapy-associated carcinogenesis in which tamoxifen-induced activation of the PI3K pathway acts as a non-genetic driver event, contributing to the multistep model of uterine carcinogenesis. While this PI3K mechanism is specific to tamoxifen-associated uterine cancer, the concept of treatment-induced signaling events may have broader applicability to other routes of tumorigenesis. 000304084 536__ $$0G:(DE-HGF)POF4-899$$a899 - ohne Topic (POF4-899)$$cPOF4-899$$fPOF IV$$x0 000304084 588__ $$aDataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de 000304084 7001_ $$aNardone, Agostina$$b1 000304084 7001_ $$aAnand, Shankara$$b2 000304084 7001_ $$aGurevich, Daniel$$b3 000304084 7001_ $$00000-0002-5739-1781$$aGao, Jianjiong$$b4 000304084 7001_ $$aDroog, Marjolein$$b5 000304084 7001_ $$00000-0002-2916-0337$$aHermida-Prado, Francisco$$b6 000304084 7001_ $$aAkhshi, Tara$$b7 000304084 7001_ $$aFeiglin, Ariel$$b8 000304084 7001_ $$aFeit, Avery S$$b9 000304084 7001_ $$aCohen Feit, Gabriella$$b10 000304084 7001_ $$aDackus, Gwen$$b11 000304084 7001_ $$aPun, Matthew$$b12 000304084 7001_ $$aKuang, Yanan$$b13 000304084 7001_ $$00000-0001-6026-2211$$aCha, Justin$$b14 000304084 7001_ $$aMiller, Mendy$$b15 000304084 7001_ $$00000-0001-9209-5403$$aGregoricchio, Sebastian$$b16 000304084 7001_ $$aLanfermeijer, Mirthe$$b17 000304084 7001_ $$aCornelissen, Sten$$b18 000304084 7001_ $$aGibson, William J$$b19 000304084 7001_ $$00000-0002-2287-5663$$aPaweletz, Cloud P$$b20 000304084 7001_ $$00000-0002-0201-4444$$aVan Allen, Eliezer M$$b21 000304084 7001_ $$avan Leeuwen, Flora E$$b22 000304084 7001_ $$00000-0002-2358-9765$$aNederlof, Petra M$$b23 000304084 7001_ $$aNguyen, Quang-Dé$$b24 000304084 7001_ $$aMourits, Marian J E$$b25 000304084 7001_ $$aRadovich, Milan$$b26 000304084 7001_ $$aLeshchiner, Ignaty$$b27 000304084 7001_ $$aStewart, Chip$$b28 000304084 7001_ $$aMatulonis, Ursula A$$b29 000304084 7001_ $$00000-0002-9823-7289$$aZwart, Wilbert$$b30 000304084 7001_ $$aMaruvka, Yosef E$$b31 000304084 7001_ $$00000-0002-0936-0753$$aGetz, Gad$$b32 000304084 7001_ $$00000-0001-7996-7529$$aJeselsohn, Rinath$$b33 000304084 773__ $$0PERI:(DE-600)1494946-5$$a10.1038/s41588-025-02308-w$$pnn$$tNature genetics$$vnn$$x1061-4036$$y2025 000304084 909CO $$ooai:inrepo02.dkfz.de:304084$$pVDB 000304084 9101_ $$0I:(DE-588b)2036810-0$$60000-0002-0342-5579$$aDeutsches Krebsforschungszentrum$$b0$$kDKFZ 000304084 9131_ $$0G:(DE-HGF)POF4-899$$1G:(DE-HGF)POF4-890$$2G:(DE-HGF)POF4-800$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bProgrammungebundene Forschung$$lohne Programm$$vohne Topic$$x0 000304084 9141_ $$y2025 000304084 915__ $$0StatID:(DE-HGF)0420$$2StatID$$aNationallizenz$$d2025-01-01$$wger 000304084 915__ $$0StatID:(DE-HGF)3003$$2StatID$$aDEAL Nature$$d2025-01-01$$wger 000304084 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2025-01-01 000304084 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2025-01-01 000304084 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2025-01-01 000304084 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2025-01-01 000304084 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2025-01-01 000304084 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences$$d2025-01-01 000304084 915__ $$0StatID:(DE-HGF)1190$$2StatID$$aDBCoverage$$bBiological Abstracts$$d2025-01-01 000304084 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2025-01-01 000304084 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2025-01-01 000304084 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bNAT GENET : 2022$$d2025-01-01 000304084 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search$$d2025-01-01 000304084 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC$$d2025-01-01 000304084 915__ $$0StatID:(DE-HGF)9930$$2StatID$$aIF >= 30$$bNAT GENET : 2022$$d2025-01-01 000304084 9201_ $$0I:(DE-He78)BE01-20160331$$kBE01$$lDKTK Koordinierungsstelle Berlin$$x0 000304084 980__ $$ajournal 000304084 980__ $$aVDB 000304084 980__ $$aI:(DE-He78)BE01-20160331 000304084 980__ $$aUNRESTRICTED