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000304084 1001_ $$00000-0002-0342-5579$$aKübler, Kirsten$$b0
000304084 245__ $$aTamoxifen induces PI3K activation in uterine cancer.
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000304084 520__ $$aMutagenic processes and clonal selection contribute to the development of therapy-associated secondary neoplasms, a known complication of cancer treatment. The association between tamoxifen therapy and secondary uterine cancers is uncommon but well established; however, the genetic mechanisms underlying tamoxifen-driven tumorigenesis remain unclear. We find that oncogenic PIK3CA mutations, common in spontaneously arising estrogen-associated de novo uterine cancer, are significantly less frequent in tamoxifen-associated tumors. In vivo, tamoxifen-induced estrogen receptor stimulation activates phosphoinositide 3-kinase (PI3K) signaling in normal mouse uterine tissue, potentially eliminating the selective benefit of PI3K-activating mutations in tamoxifen-associated uterine cancer. Together, we present a unique pathway of therapy-associated carcinogenesis in which tamoxifen-induced activation of the PI3K pathway acts as a non-genetic driver event, contributing to the multistep model of uterine carcinogenesis. While this PI3K mechanism is specific to tamoxifen-associated uterine cancer, the concept of treatment-induced signaling events may have broader applicability to other routes of tumorigenesis.
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000304084 7001_ $$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
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