Related Experiment Video

Updated: Sep 18, 2025

Evaluating the Differentiation Capacity of Mouse Prostate Epithelial Cells Using Organoid Culture
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Evaluating the Differentiation Capacity of Mouse Prostate Epithelial Cells Using Organoid Culture

Published on: November 22, 2019

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Divergent FOXA1 mutations drive prostate tumorigenesis and therapy-resistant cellular plasticity

Sanjana Eyunni1,2,3, Rahul Mannan1,2, Yuping Zhang1,2

  • 1Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

Science (New York, N.Y.)
|June 26, 2025
PubMed

Insights

Distinct FOXA1 mutations drive prostate cancer progression. Class 1 mutations promote androgen-dependent tumors, while Class 2 mutations enable therapy resistance by reprogramming cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Forkhead box A1 (FOXA1) is frequently altered in prostate cancer, but its in vivo oncogenic roles are unclear.
  • Understanding FOXA1's function is crucial for developing targeted prostate cancer therapies.

Purpose of the Study:

  • To elucidate the in vivo oncogenic mechanisms of distinct FOXA1 mutations in prostate cancer.
  • To investigate how different FOXA1 alterations contribute to tumor initiation and progression.

Main Methods:

  • Development of knock-in mouse models for specific FOXA1 mutations.
  • Histopathological and multiomic analyses of prostate tissues and organoids.
  • Investigation of signaling pathways including mTOR, AR, KLF5, and AP-1.

Main Results:

  • Class 1 FOXA1 mutations with p53 inactivation drive androgen-dependent prostate adenocarcinomas via mTORC1/2 and AR coactivation.
  • Class 2 FOXA1 mutations induce luminal cell reprogramming to a progenitor-like state, activating KLF5 and AP-1.
  • Class 2 mutations promote cell survival and proliferation, even under low androgen conditions, suggesting therapy resistance.

Conclusions:

  • FOXA1 acts as a multifaceted oncogene in prostate cancer.
  • Distinct FOXA1 mutation classes employ divergent strategies to drive tumorigenesis and therapy-resistant progression.

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