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Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer
Open accessAbstract
Abtract Forkhead box A1 (FOXA1) is a pioneer transcription factor that is essential for the normal development of several endoderm-derived organs, including the prostate gland 1,2. FOXA1 is frequently mutated in hormone-receptor-driven prostate, breast, bladder and salivary-gland tumours 3-8. However, it is unclear how FOXA1 alterations affect the development of cancer, and FOXA1 has previously been ascribed both tumour-suppressive 9-11 and oncogenic 12-14 roles. Here we assemble an aggregate cohort of 1,546 prostate cancers and show that FOXA1 alterations fall into three structural classes that diverge in clinical incidence and genetic co-alteration profiles, with a collective prevalence of 35%. Class-1 activating mutations originate in early prostate cancer without alterations in ETS or SPOP, selectively recur within the wing-2 region of the DNA-binding forkhead domain, enable enhanced chromatin mobility and binding frequency, and strongly transactivate a luminal androgen-receptor program of prostate oncogenesis. By contrast, class-2 activating mutations are acquired in metastatic prostate cancers, truncate the C-terminal domain of FOXA1, enable dominant chromatin binding by increasing DNA affinity and-through TLE3 inactivation-promote metastasis driven by the WNT pathway. Finally, class-3 genomic rearrangements are enriched in metastatic prostate cancers, consist of duplications and translocations within the FOXA1 locus, and structurally reposition a conserved regulatory element-herein denoted FOXA1 mastermind (FOXMIND)-to drive overexpression of FOXA1 or other oncogenes. Our study reaffirms the central role of FOXA1 in mediating oncogenesis driven by the androgen receptor, and provides mechanistic insights into how the classes of FOXA1 alteration promote the initiation and/or metastatic progression of prostate cancer. These results have direct implications for understanding the pathobiology of other hormone-receptor-driven cancers and rationalize the co-targeting of FOXA1 activity in therapeutic strategies.
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“many key genes that drive PCa, such as FOXA1 or HOXB13 (refs. 7,8), promote tumor progression by regulating how AR binds to or activates its target genes.”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [8]
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Metadata
- Authors
- Parolia, A., Cieslik, M., Chu, S.-C., Xiao, L., Ouchi, T., Zhang, Y., Wang, X., Vats, P., Cao, X., Pitchiaya, S., Su, F., Wang, R., Feng, F. Y., Wu, Y.-M., Lonigro, R. J., Robinson, D. R., & Chinnaiyan, A. M.
- Affiliations
- University of Michigan (US)
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- Corresponding author
- Chinnaiyan, Arul M.
- ORCID
- Venue
- Nature
- Published
- 2019-06-26
- Volume
- 571
- Issue
- 7765
- Pages
- 413-418
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6661908
- OpenAlex
- W2955719861
- Cited by
- 284
- References
- 60
- Citations by year
- 2026: 25 · 2025: 40 · 2024: 34 · 2023: 44 · 2022: 47 · 2021: 50 · 2020: 35 · 2019: 9
- FWCI
- 25.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (F99CA245825, R35CA231996, U01CA214170, P50CA186786)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- FOXA1, prostate cancer, activating mutations, androgen receptor, chromatin binding, metastasis, Wnt signaling, TLE3, genome rearrangement, ETS transcription factors, SPOP, carcinogenesis
- MeSH terms
- Protein Domains, Chromatin, Humans, Male, Models, Molecular, Mutation, Neoplasm Metastasis, Prostatic Neoplasms, Receptors, Androgen, Genome, Human, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Hepatocyte Nuclear Factor 3-alpha, Wnt Signaling Pathway
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