SPOP mutation drives prostate tumorigenesis in vivo through coordinate regulation of PI3K/mTOR and AR signaling
Open accessAbstract
Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe a mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia and invasive, poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer. Using these models and human prostate cancer samples, we show that SPOP mutation activates both PI3K/mTOR and androgen receptor signaling, effectively uncoupling the normal negative feedback between these two pathways.
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SPOP mutations lead to abnormal activation of AR and AKT-mTORC1 signaling pathways.
“These mutations lead to abnormal activation of the androgen receptor (AR) and AKT-mTORC1 signaling pathways (Blattner et al., 2017).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Blattner et al., 2017
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References 52 · Cited by 204
- Authors
- Blattner, M., Liu, D., Robinson, B. D., Huang, D., Poliakov, A., Gao, D., Nataraj, S., Deonarine, L. D., Augello, M. A., Sailer, V., Ponnala, L., Ittmann, M., Chinnaiyan, A. M., Sboner, A., Chen, Y., Rubin, M. A., & Barbieri, C. E.
- Affiliations
- Weill Cornell Medicine (US)
- Cornell University (US)
- University of Michigan (US)
- Memorial Sloan Kettering Cancer Center (US)
- Baylor College of Medicine (US)
- Howard Hughes Medical Institute (US)
- NewYork–Presbyterian Hospital (US)
- Corresponding author
- Rubin, Mark A.
- Barbieri, Christopher E.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 31
- Issue
- 3
- Pages
- 436-451
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC5384998
- OpenAlex
- W2595754822
- Cited by
- 204
- References
- 52
- Citations by year
- 2026: 17 · 2025: 15 · 2024: 15 · 2023: 18 · 2022: 21 · 2021: 35 · 2020: 22 · 2019: 27 · 2018: 25 · 2017: 8
- FWCI
- 18.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- BORIS (University Library Bern) (submittedVersion)
- Funders
- National Cancer Institute (2R01CA125612-05A1, K08CA140946, K08CA187417-01, P30CA008748, P50CA092629, R01CA193837)
- Prostate Cancer Foundation
- Geoffrey Beene Cancer Research Center
- Gerstner Family Foundation
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › 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 › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- SPOP mutations, prostate cancer, prostate tumorigenesis, PI3K/mTOR signaling, androgen receptor signaling, PTEN loss, prostatic intraepithelial neoplasia, prostate organoids, negative feedback loop, mouse model
- MeSH terms
- Animals, Humans, Male, Mutation, Nuclear Proteins, Prostatic Neoplasms, Receptors, Androgen, Repressor Proteins, Signal Transduction, Phosphatidylinositol 3-Kinases, Cell Proliferation, Proto-Oncogene Proteins c-ets, PTEN Phosphohydrolase, Mice, Nuclear Receptor Coactivator 3, TOR Serine-Threonine Kinases
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