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

doi:10.1101/gad.304261.117

	Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase
	Zhang, Siwei 1,2; Fan, Gaofeng1,3 ; Hao, Yuan 1; Hammell, Molly 1; Wilkinson, John Erby 4; Tonks, Nicholas K.1
	2017-10
发表期刊	GENES & DEVELOPMENT (IF:7.5[JCR-2023],10.5[5-Year])
ISSN	0890-9369
卷号	31 期号:19 页码:1939-1957
发表状态	已发表
DOI	10.1101/gad.304261.117
摘要	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 1D beta 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.
关键词	FYN PTPN23 breast cancer tumor suppressor tyrosine phosphorylation
收录类别	SCI
语种	英语
资助项目	Cold Spring Harbor Laboratory Cancer Centre Support Grant[CA45508]
WOS研究方向	Cell Biology ; Developmental Biology ; Genetics & Heredity
WOS类目	Cell Biology ; Developmental Biology ; Genetics & Heredity
WOS记录号	WOS:000414054000003
出版者	COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
WOS关键词	MAMMARY EPITHELIAL-CELLS ; HD-PTP ; CHROMOSOME 3P21.3 ; PROGENITOR CELLS ; PROSTATE-CANCER ; HUMAN GENOME ; IN-VITRO ; SRC ; EXPRESSION ; GENE
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/9879
专题	生命科学与技术学院_PI研究组_范高峰组
通讯作者	Tonks, Nicholas K.
作者单位	1.Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA 2.SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 4.Univ Michigan, Dept Pathol, Unit Lab Anim Med, Ann Arbor, MI 48109 USA
推荐引用方式 GB/T 7714	Zhang, Siwei,Fan, Gaofeng,Hao, Yuan,et al. Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase[J]. GENES & DEVELOPMENT,2017,31(19):1939-1957.
APA	Zhang, Siwei,Fan, Gaofeng,Hao, Yuan,Hammell, Molly,Wilkinson, John Erby,&Tonks, Nicholas K..(2017).Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase.GENES & DEVELOPMENT,31(19),1939-1957.
MLA	Zhang, Siwei,et al."Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase".GENES & DEVELOPMENT 31.19(2017):1939-1957.