Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase

Zhang, S., Fan, G., Hao, Y., Hammell, M., Wilkinson, J. E., Tonks, N. K. (October 2017) Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase. Genes Dev, 31 (19). pp. 1939-57. ISSN 0890-9369

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Abstract

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 1Dbeta 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 beta-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.

Item Type:	Paper
Uncontrolled Keywords:	Fyn Ptpn23 breast cancer tumor suppressor tyrosine phosphorylation
Subjects:	diseases & disorders > cancer > cancer types > breast cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > tumor suppressor bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein tyrosine phosphatase
CSHL Authors:	Tonks, Nicholas K. Hammell, Molly Zhang, Siwei Fan, Gaofeng Hao, Yuan
Communities:	CSHL Cancer Center Program > Gene Regulation and Cell Proliferation CSHL Cancer Center Program > Signal Transduction CSHL labs > Hammell M. lab CSHL labs > Tonks lab CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program
Depositing User:	Matt Covey
Date:	1 October 2017
Date Deposited:	30 Oct 2017 18:32
Last Modified:	15 Nov 2023 18:18
PMCID:	PMC5710140
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/35651

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