Evidence map›Paper›PMID 40846762›Full record

ArticleNature genetics2025

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 and 24 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed.

  1. Integrated Clinicogenomic Risk Modeling for Metachronous Second Primary Cancers.medRxiv : the preprint server for health sciences · 2026
    Article
  2. Article
  3. Article
  4. Article
  5. Tamoxifen takes the wheel.Nature reviews. Cancer · 2025
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

34 authors.

Kirsten Kübler *Broad Institute of MIT and Harvard, Cambridge, MA, USA. kirsten.kuebler@bih-charite.de.ORCID http://orcid.org/0000-0002-0342-5579
Agostina Nardone *Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
Shankara AnandBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Daniel GurevichBiotechnology and Food Engineering, Technion, Haifa, Israel.
Jianjiong GaoCaris Life Sciences, Phoenix, AZ, USA.ORCID http://orcid.org/0000-0002-5739-1781
Marjolein DroogDivision of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Francisco Hermida-PradoCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0002-2916-0337
Tara AkhshiCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
Ariel FeiglinDepartment of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Avery S FeitCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
Gabriella Cohen FeitCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
Gwen DackusDivision of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Matthew PunCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
Yanan KuangBelfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
Justin ChaBroad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-6026-2211
Mendy MillerBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Sebastian GregoricchioDivision of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands.ORCID http://orcid.org/0000-0001-9209-5403
Mirthe LanfermeijerDepartment of Laboratory Medicine, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Sten CornelissenCore Facility Molecular Pathology & Biobanking, Netherlands Cancer Institute, Amsterdam, the Netherlands.
William J GibsonBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Cloud P PaweletzBelfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0002-2287-5663
Eliezer M Van AllenBroad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-0201-4444
Flora E van LeeuwenDepartment of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Petra M NederlofDepartment of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.ORCID http://orcid.org/0000-0002-2358-9765
Quang-Dé NguyenLurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Marian J E MouritsDepartment of Gynecological Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Milan RadovichCaris Life Sciences, Phoenix, AZ, USA.
Ignaty LeshchinerBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Chip StewartBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Ursula A MatulonisHarvard Medical School, Boston, MA, USA.
Wilbert ZwartDivision of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands.ORCID http://orcid.org/0000-0002-9823-7289
Yosef E MaruvkaBiotechnology and Food Engineering, Technion, Haifa, Israel.
Gad GetzBroad Institute of MIT and Harvard, Cambridge, MA, USA. gadgetz@broadinstitute.org.ORCID http://orcid.org/0000-0002-0936-0753
Rinath JeselsohnBroad Institute of MIT and Harvard, Cambridge, MA, USA. rinath_jeselsohn@dfci.harvard.edu.ORCID http://orcid.org/0000-0001-7996-7529

Funding

Project 2: Combined personal neoantigen-targeting cancer vaccines with immune checkpoint blockade for ovarian cancerP50CA240243 · NCI · DANA-FARBER CANCER INST · PI SHAPIRO, GEOFFREY I · 2020 to 2024
$11.5M
Optimizing CDK7 Inhibitor Therapeutic Strategies for ER+ Breast CancerR01CA237414 · NCI · DANA-FARBER CANCER INST · PI Rinath M. Jeselsohn · 2019 to 2026
$2.3M
Elucidating and overcoming endocrine resistance driven by ESR1 mutationsK08CA191058 · NCI · DANA-FARBER CANCER INST · PI JESELSOHN, RINATH M. · 2015 to 2019
$886k
NCI NIH HHS K08 CA191058NCI NIH HHS P50 CA240243NCI NIH HHS R01 CA237414United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP) W81XWH-17-1-0084U.S. Department of Defense (United States Department of Defense) W81XWH-17-1-0084U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) 5K08CA191058-05U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) P50CA240243
6 · The paper itself

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.

Indexed as

Carcinoma, EndometrioidClass I Phosphatidylinositol 3-KinasesSelective Estrogen Receptor ModulatorsTamoxifenUterine NeoplasmsAnimalsBreast NeoplasmsClass Ia Phosphatidylinositol 3-KinaseDNA Mutational AnalysisEnzyme ActivationExome SequencingFemaleHumansMiceThiazolesAlpelisibClass Ia Phosphatidylinositol 3-KinaseClass I Phosphatidylinositol 3-KinasesPIK3CA protein, humanPIK3R1 protein, humanSelective Estrogen Receptor ModulatorsTamoxifenThiazoles

Identifiers

PMID40846762
PMCPMC12425819

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.