Journal Article

DKFZ-2025-01752

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Tamoxifen induces PI3K activation in uterine cancer.

Kübler, K.DKFZ* ; Nardone, A. ; Anand, S. ; Gurevich, D. ; Gao, J. ; Droog, M. ; Hermida-Prado, F. ; Akhshi, T. ; Feiglin, A. ; Feit, A. S. ; Cohen Feit, G. ; Dackus, G. ; Pun, M. ; Kuang, Y. ; Cha, J. ; Miller, M. ; Gregoricchio, S. ; Lanfermeijer, M. ; Cornelissen, S. ; Gibson, W. J. ; Paweletz, C. P. ; Van Allen, E. M. ; van Leeuwen, F. E. ; Nederlof, P. M. ; Nguyen, Q.-D. ; Mourits, M. J. E. ; Radovich, M. ; Leshchiner, I. ; Stewart, C. ; Matulonis, U. A. ; Zwart, W. ; Maruvka, Y. E. ; Getz, G. ; Jeselsohn, R.

2025
Macmillan Publishers Limited, part of Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41588-025-02308-w

Abstract: 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.

Note: 2025 Sep;57(9):2192-2202

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Berlin (BE01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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