Tamoxifen induces PI3K activation in uterine cancer

Kirsten Kübler; Agostina Nardone; Shankara Anand; Daniel Gurevich; Jianjiong Gao; Marjolein Droog; Francisco Hermida-Prado; Tara Akhshi; Ariel Feiglin; Avery S. Feit; Gabriella Cohen Feit; Gwen Dackus; Matthew Pun; Yanan Kuang; Justin Cha; Mendy Miller; Sebastian Gregoricchio; Mirthe Lanfermeijer; Sten Cornelissen; William J. Gibson; Cloud P. 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 Zwart; Yosef E. Maruvka; Gad Getz; Rinath Jeselsohn

doi:10.1038/s41588-025-02308-w

Tamoxifen induces PI3K activation in uterine cancer

Kirsten Kübler (Corresponding author), Agostina Nardone, Shankara Anand, Daniel Gurevich, Jianjiong Gao, Marjolein Droog, Francisco Hermida-Prado, Tara Akhshi, Ariel Feiglin, Avery S. Feit, Gabriella Cohen Feit, Gwen Dackus, Matthew Pun, Yanan Kuang, Justin Cha, Mendy Miller, Sebastian Gregoricchio, Mirthe Lanfermeijer, Sten Cornelissen, William J. GibsonCloud P. 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 Zwart, Yosef E. Maruvka, Gad Getz (Corresponding author), Rinath Jeselsohn (Corresponding author)

Chemical Biology

Research output: Contribution to journal › Article › Academic › peer-review

1 Citation (Scopus)

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.

Original language	English
Pages (from-to)	2192-2202
Number of pages	11
Journal	Nature Genetics
Volume	57
Issue number	9
DOIs	https://doi.org/10.1038/s41588-025-02308-w
Publication status	Published - 22 Aug 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

Keywords

Enzyme Activation
Uterine Neoplasms/chemically induced
Tamoxifen/adverse effects
Breast Neoplasms/drug therapy
Selective Estrogen Receptor Modulators/adverse effects
Exome Sequencing
Humans
Female
Animals
Mice
Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors
DNA Mutational Analysis
Carcinoma, Endometrioid/chemically induced
Thiazoles
Class Ia Phosphatidylinositol 3-Kinase

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41588-025-02308-w

pdfFinal published version, 4.81 MBLicence: CC BY

Cite this

Kübler, K., 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., ... Jeselsohn, R. (2025). Tamoxifen induces PI3K activation in uterine cancer. Nature Genetics, 57(9), 2192-2202. https://doi.org/10.1038/s41588-025-02308-w

@article{e70ec3ac9e7847a5aa1877c7a144cb81,

title = "Tamoxifen induces PI3K activation in uterine cancer",

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.",

keywords = "Enzyme Activation, Uterine Neoplasms/chemically induced, Tamoxifen/adverse effects, Breast Neoplasms/drug therapy, Selective Estrogen Receptor Modulators/adverse effects, Exome Sequencing, Humans, Female, Animals, Mice, Class I Phosphatidylinositol 3-Kinases/antagonists \& inhibitors, DNA Mutational Analysis, Carcinoma, Endometrioid/chemically induced, Thiazoles, Class Ia Phosphatidylinositol 3-Kinase",

author = "Kirsten K{\"u}bler and Agostina Nardone and Shankara Anand and Daniel Gurevich and Jianjiong Gao and Marjolein Droog and Francisco Hermida-Prado and Tara Akhshi and Ariel Feiglin and Feit, \{Avery S.\} and \{Cohen Feit\}, Gabriella and Gwen Dackus and Matthew Pun and Yanan Kuang and Justin Cha and Mendy Miller and Sebastian Gregoricchio and Mirthe Lanfermeijer and Sten Cornelissen and Gibson, \{William J.\} and Paweletz, \{Cloud P.\} and \{Van Allen\}, \{Eliezer M.\} and \{van Leeuwen\}, \{Flora E.\} and Nederlof, \{Petra M.\} and Nguyen, \{Quang D{\'e}\} and Mourits, \{Marian J.E.\} and Milan Radovich and Ignaty Leshchiner and Chip Stewart and Matulonis, \{Ursula A.\} and Wilbert Zwart and Maruvka, \{Yosef E.\} and Gad Getz and Rinath Jeselsohn",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = aug,

day = "22",

doi = "10.1038/s41588-025-02308-w",

language = "English",

volume = "57",

pages = "2192--2202",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

}

Kübler, K, Nardone, A, Anand, S, Gurevich, D, Gao, J, Droog, M, Hermida-Prado, F, Akhshi, T, Feiglin, A, Feit, AS, Cohen Feit, G, Dackus, G, Pun, M, Kuang, Y, Cha, J, Miller, M, Gregoricchio, S, Lanfermeijer, M, Cornelissen, S, Gibson, WJ, Paweletz, CP, Van Allen, EM, van Leeuwen, FE, Nederlof, PM, Nguyen, QD, Mourits, MJE, Radovich, M, Leshchiner, I, Stewart, C, Matulonis, UA, Zwart, W, Maruvka, YE, Getz, G & Jeselsohn, R 2025, 'Tamoxifen induces PI3K activation in uterine cancer', Nature Genetics, vol. 57, no. 9, pp. 2192-2202. https://doi.org/10.1038/s41588-025-02308-w

TY - JOUR

T1 - Tamoxifen induces PI3K activation in uterine cancer

AU - Kübler, Kirsten

AU - Nardone, Agostina

AU - Anand, Shankara

AU - Gurevich, Daniel

AU - Gao, Jianjiong

AU - Droog, Marjolein

AU - Hermida-Prado, Francisco

AU - Akhshi, Tara

AU - Feiglin, Ariel

AU - Feit, Avery S.

AU - Cohen Feit, Gabriella

AU - Dackus, Gwen

AU - Pun, Matthew

AU - Kuang, Yanan

AU - Cha, Justin

AU - Miller, Mendy

AU - Gregoricchio, Sebastian

AU - Lanfermeijer, Mirthe

AU - Cornelissen, Sten

AU - Gibson, William J.

AU - Paweletz, Cloud P.

AU - Van Allen, Eliezer M.

AU - van Leeuwen, Flora E.

AU - Nederlof, Petra M.

AU - Nguyen, Quang Dé

AU - Mourits, Marian J.E.

AU - Radovich, Milan

AU - Leshchiner, Ignaty

AU - Stewart, Chip

AU - Matulonis, Ursula A.

AU - Zwart, Wilbert

AU - Maruvka, Yosef E.

AU - Getz, Gad

AU - Jeselsohn, Rinath

PY - 2025/8/22

Y1 - 2025/8/22

N2 - 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.

AB - 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.

KW - Enzyme Activation

KW - Uterine Neoplasms/chemically induced

KW - Tamoxifen/adverse effects

KW - Breast Neoplasms/drug therapy

KW - Selective Estrogen Receptor Modulators/adverse effects

KW - Exome Sequencing

KW - Humans

KW - Female

KW - Animals

KW - Mice

KW - Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors

KW - DNA Mutational Analysis

KW - Carcinoma, Endometrioid/chemically induced

KW - Thiazoles

KW - Class Ia Phosphatidylinositol 3-Kinase

UR - https://www.scopus.com/pages/publications/105013817013

U2 - 10.1038/s41588-025-02308-w

DO - 10.1038/s41588-025-02308-w

M3 - Article

C2 - 40846762

AN - SCOPUS:105013817013

SN - 1061-4036

VL - 57

SP - 2192

EP - 2202

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

Tamoxifen induces PI3K activation in uterine cancer

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this