SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia
Open accessAbstract
Loss of cellular polarity is a hallmark of epithelial cancers, raising the possibility that regulators of polarity have a role in suppressing tumorigenesis. The Scribble complex is one of at least three interacting protein complexes that have a critical role in establishing and maintaining epithelial polarity. In human colorectal, breast, and endometrial cancers, expression of the Scribble complex member SCRIB is often mislocalized and deregulated. Here, we report that Scrib is indispensable for prostate homeostasis in mice. Scrib heterozygosity initiated prostate hyperplasia, while targeted biallelic Scrib loss predisposed mice to prostate intraepithelial neoplasia. Mechanistically, Scrib was shown to negatively regulate the MAPK cascade to suppress tumorigenesis. Further analysis revealed that prostate-specific loss of Scrib in mice combined with expression of an oncogenic Kras mutation promoted the progression of prostate cancer that recapitulated the human disease. The clinical significance of the work in mice was highlighted by our observation that SCRIB deregulation strongly correlated with poor survival in human prostate cancer. These data suggest that the polarity network could provide a new avenue for therapeutic intervention.
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Loss of SCRIB expression functions as a tumor suppressor in Drosophila and mammals.
“Loss of SCRIB that results in uncontrolled proliferation and tissue growth identifying it as tumor suppressor (1).”
From Mislocalization of the Cell Polarity Protein Scribble Promotes Mammary Tumorigenesis and Is Associated with Basal Breast Cancer (2014) · cites this paper as [3]
In several human cancers-breast, prostate, and colon-hSCRIB protein is mislocalized away from cell-cell junctions.
“hSCRIB protein is mislocalized from cell-cell junctions in multiple human cancers, including breast, prostate and colon (2, 3).”
From Mislocalization of the Cell Polarity Protein Scribble Promotes Mammary Tumorigenesis and Is Associated with Basal Breast Cancer (2014) · cites this paper as [3]
Prostate cancer patients with hSCRIB mislocalization have worse survival.
“In prostate cancer, hSCRIB mislocalization is correlated with poor patient survival (3).”
From Mislocalization of the Cell Polarity Protein Scribble Promotes Mammary Tumorigenesis and Is Associated with Basal Breast Cancer (2014) · cites this paper as [3]
Loss or downregulation of SCRIB acts as a tumor suppressor by inhibiting cell death or inducing proliferation.
“Others and we have previously reported that downregulation (or loss) of SCRIB expression functions as a tumor suppressor by inhibiting cell death or inducing proliferation (2, 3).”
From Mislocalization of the Cell Polarity Protein Scribble Promotes Mammary Tumorigenesis and Is Associated with Basal Breast Cancer (2014) · cites this paper as [3]
Scribble knockout mice die as neonates, and although they have severely impaired neural tube and abdominal wall closure; gonadal defects; and a disorganized, hyperplastic neuroepithelium in the cortex and other parts of the nervous system, other tissues are relatively normal.
“Scribble knockout mice die as neonates, and although they have severely impaired neural tube and abdominal wall closure; gonadal defects; and a disorganized, hyperplastic neuroepithelium in the cortex and other parts of the nervous system, other tissues are relatively normal (Murdoch et al., 2003; Zarbalis et al., 2004; Pearson et al., 2011).”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Pearson et al., 2011
Many aspects of early to mid-embryonic mouse development proceed relatively normally in scribble mutants, from implantation through gastrulation and on to organogenesis.
“Many aspects of early to mid-embryonic mouse development proceed relatively normally in scribble mutants, from implantation through gastrulation and on to organogenesis.”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Pearson et al., 2011
Conditional Scribble knockout in the prostate epithelium does not disrupt prostate development.
“Conditional Scribble knockout in the prostate epithelium does not disrupt prostate development (Pearson et al., 2011), whereas conditional knockout in the developing skin reveals only a transient delay in formation of the permeability barrier during embryonic development, which later resolves (Pearson et al., 2015).”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Pearson et al., 2011
In several cases, conditional knockout or heterozygosity of Scribble accelerates tumorigenesis, e.g., leading to multifocal prostate hyperplasia, and accelerated skin and lung tumorigenesis.
“In several cases, conditional knockout or heterozygosity does accelerate tumorigenesis, e.g., leading to multifocal prostate hyperplasia (Pearson et al., 2011), and accelerated skin and lung tumorigenesis (Elsum et al., 2014; Pearson et al., 2015).”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Pearson et al., 2011
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Elsum, I. A., & Humbert, P. O. (2013) · Cells Tissues Organs · doi:10.1159/000348423 · Cited by 27 · see citing works
Self-citationThe cell fate determinant Scribble is required for maintenance of hematopoietic stem cell function
Mohr, J., Dash, B. P., Schnoeder, T. M., Wolleschak, D., Herzog, C., Tubio Santamaria, N., Weinert, S., Godavarthy, S., Zanetti, C., Naumann, M., et al. (2018) · Leukemia · doi:10.1038/s41375-018-0025-0 · Cited by 23 · see citing works
Scribble sub-cellular localization modulates recruitment of YES1 to regulate YAP1 phosphorylation
Zhao, D., Yin, Z., Soellner, M. B., & Martin, B. R. (2021) · Cell Chemical Biology · doi:10.1016/j.chembiol.2021.02.019 · Cited by 22 · see citing works
How, J. Y., Caria, S., Humbert, P. O., & Kvansakul, M. (2019) · FEBS Letters · doi:10.1002/1873-3468.13329 · Cited by 19 · see citing works
Self-citationWölwer, C. B., Gödde, N., Pase, L. B., Elsum, I. A., Lim, K. Y. B., Sacirbegovic, F., Walkley, C. R., Ellis, S., Ohno, S., Matsuzaki, F., et al. (2017) · PLOS ONE · doi:10.1371/journal.pone.0170295 · Cited by 6 · see citing works
Self-citation
- Authors
- Pearson, H. B., Perez-Mancera, P. A., Dow, L. E., Ryan, A., Tennstedt, P., Bogani, D., Elsum, I., Greenfield, A., Tuveson, D. A., Simon, R., & Humbert, P. O.
- Affiliations
- Peter MacCallum Cancer Centre (AU)
- Cold Spring Harbor Laboratory (US)
- TissuPath (AU)
- University Medical Center Hamburg-Eppendorf (DE)
- Medical Research Council (GB)
- Cancer Research UK (GB)
- The University of Melbourne (AU)
- Corresponding author
- Humbert, Patrick O.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2011-11-01
- Volume
- 121
- Issue
- 11
- Pages
- 4257-4267
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3223862
- OpenAlex
- W2085000020
- Cited by
- 185
- References
- 58
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 9 · 2020: 7 · 2019: 13 · 2018: 15 · 2017: 20 · 2016: 9 · 2015: 22 · 2014: 15 · 2013: 24 · 2012: 16
- FWCI
- 15.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Funders
- Prostate Cancer Foundation
- Cancer Research UK
- Prostate Cancer Foundation of Australia
- Fundación Caja Madrid
- Hutchison Whampoa Limited
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- SCRIB, epithelial polarity, prostate cancer, prostatic hyperplasia, prostatic intraepithelial neoplasia, MAPK signaling, KRAS mutation, tumor progression, prognosis, tumor suppressor
- MeSH terms
- Animals, Base Sequence, Disease Models, Animal, Heterozygote, Humans, Male, Membrane Proteins, Mutation, Prostatic Neoplasms, Genes, ras, RNA, Messenger, RNA, Neoplasm, Mice, Knockout, Disease Progression, Prostatic Intraepithelial Neoplasia, MAP Kinase Signaling System, Tumor Suppressor Proteins, Tissue Array Analysis, Intracellular Signaling Peptides and Proteins, Mice, Kaplan-Meier Estimate, Gene Knockout Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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