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Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase
Disruption of the balanced modulation of reversible tyrosine phosphorylation has been implicated in the etiology of various human cancers, including breast cancer. Protein Tyrosine Phosphatase N23 (PTPN23) resides in chromosomal region 3p21.3, which is hemizygously or homozygously lost in some breas...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710140/ https://www.ncbi.nlm.nih.gov/pubmed/29066500 http://dx.doi.org/10.1101/gad.304261.117 |
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author | Zhang, Siwei Fan, Gaofeng Hao, Yuan Hammell, Molly Wilkinson, John Erby Tonks, Nicholas K. |
author_facet | Zhang, Siwei Fan, Gaofeng Hao, Yuan Hammell, Molly Wilkinson, John Erby Tonks, Nicholas K. |
author_sort | Zhang, Siwei |
collection | PubMed |
description | Disruption of the balanced modulation of reversible tyrosine phosphorylation has been implicated in the etiology of various human cancers, including breast cancer. Protein Tyrosine Phosphatase N23 (PTPN23) resides in chromosomal region 3p21.3, which is hemizygously or homozygously lost in some breast cancer patients. In a loss-of-function PTPome screen, our laboratory identified PTPN23 as a suppressor of cell motility and invasion in mammary epithelial and breast cancer cells. Now, our TCGA (The Cancer Genome Atlas) database analyses illustrate a correlation between low PTPN23 expression and poor survival in breast cancers of various subtypes. Therefore, we investigated the tumor-suppressive function of PTPN23 in an orthotopic transplantation mouse model. Suppression of PTPN23 in Comma 1Dβ cells induced breast tumors within 56 wk. In PTPN23-depleted tumors, we detected hyperphosphorylation of the autophosphorylation site tyrosine in the SRC family kinase (SFK) FYN as well as Tyr142 in β-catenin. We validated the underlying mechanism of PTPN23 function in breast tumorigenesis as that of a key phosphatase that normally suppresses the activity of FYN in two different models. We demonstrated that tumor outgrowth from PTPN23-deficient BT474 cells was suppressed in a xenograft model in vivo upon treatment with AZD0530, an SFK inhibitor. Furthermore, double knockout of FYN and PTPN23 via CRISPR/CAS9 also attenuated tumor outgrowth from PTPN23 knockout Cal51 cells. Overall, this mechanistic analysis of the tumor-suppressive function of PTPN23 in breast cancer supports the identification of FYN as a therapeutic target for breast tumors with heterozygous or homozygous loss of PTPN23. |
format | Online Article Text |
id | pubmed-5710140 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-57101402018-04-01 Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase Zhang, Siwei Fan, Gaofeng Hao, Yuan Hammell, Molly Wilkinson, John Erby Tonks, Nicholas K. Genes Dev Research Paper Disruption of the balanced modulation of reversible tyrosine phosphorylation has been implicated in the etiology of various human cancers, including breast cancer. Protein Tyrosine Phosphatase N23 (PTPN23) resides in chromosomal region 3p21.3, which is hemizygously or homozygously lost in some breast cancer patients. In a loss-of-function PTPome screen, our laboratory identified PTPN23 as a suppressor of cell motility and invasion in mammary epithelial and breast cancer cells. Now, our TCGA (The Cancer Genome Atlas) database analyses illustrate a correlation between low PTPN23 expression and poor survival in breast cancers of various subtypes. Therefore, we investigated the tumor-suppressive function of PTPN23 in an orthotopic transplantation mouse model. Suppression of PTPN23 in Comma 1Dβ cells induced breast tumors within 56 wk. In PTPN23-depleted tumors, we detected hyperphosphorylation of the autophosphorylation site tyrosine in the SRC family kinase (SFK) FYN as well as Tyr142 in β-catenin. We validated the underlying mechanism of PTPN23 function in breast tumorigenesis as that of a key phosphatase that normally suppresses the activity of FYN in two different models. We demonstrated that tumor outgrowth from PTPN23-deficient BT474 cells was suppressed in a xenograft model in vivo upon treatment with AZD0530, an SFK inhibitor. Furthermore, double knockout of FYN and PTPN23 via CRISPR/CAS9 also attenuated tumor outgrowth from PTPN23 knockout Cal51 cells. Overall, this mechanistic analysis of the tumor-suppressive function of PTPN23 in breast cancer supports the identification of FYN as a therapeutic target for breast tumors with heterozygous or homozygous loss of PTPN23. Cold Spring Harbor Laboratory Press 2017-10-01 /pmc/articles/PMC5710140/ /pubmed/29066500 http://dx.doi.org/10.1101/gad.304261.117 Text en © 2017 Zhang et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Paper Zhang, Siwei Fan, Gaofeng Hao, Yuan Hammell, Molly Wilkinson, John Erby Tonks, Nicholas K. Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase |
title | Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase |
title_full | Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase |
title_fullStr | Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase |
title_full_unstemmed | Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase |
title_short | Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase |
title_sort | suppression of protein tyrosine phosphatase n23 predisposes to breast tumorigenesis via activation of fyn kinase |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710140/ https://www.ncbi.nlm.nih.gov/pubmed/29066500 http://dx.doi.org/10.1101/gad.304261.117 |
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