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Suppression of Protein Tyrosine Phosphatase N23 Predisposes to Breast Tumorigenesis Via Activation of FYN Kinase

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Suppression of Protein Tyrosine Phosphatase N23 Predisposes to Breast Tumorigenesis Via Activation of FYN Kinase Downloaded from genesdev.cshlp.org on November 3, 2017 - Published by Cold Spring Harbor Laboratory Press Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase Siwei Zhang,1,2 Gaofeng Fan,1,3 Yuan Hao,1 Molly Hammell,1 John Erby Wilkinson,4 and Nicholas K. Tonks1 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; 2Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA; 3School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; 4Unit for Laboratory Animal Medicine, Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA 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 illus- trate 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 tu- morigenesis 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. [Keywords: FYN; PTPN23; breast cancer; tumor suppressor; tyrosine phosphorylation] Supplemental material is available for this article. Received July 5, 2017; revised version accepted October 6, 2017. The dynamic regulation of phosphorylation of tyrosyl fully. Chromosomal aberrations, copy number variations, residues in proteins is maintained by the synchronized and mutations have also been characterized in several and complementary activity of two enzyme families: pro- PTP genes in human cancer; in fact, now there are several tein tyrosine kinases (PTKs) and protein tyrosine phos- examples of PTPs as tumor suppressors or the products of phatases (PTPs). Disturbance of their functions disrupts oncogenes (Alonso et al. 2004; Ostman et al. 2006; Julien the balance of reversible tyrosine phosphorylation, which et al. 2011; Zhao et al. 2015). Nevertheless, the mechanis- impacts the normal patterns of intercellular and intracel- tic definition of the function of the majority of individual lular signals and has been implicated in the etiology of PTPs remains to be established. various human diseases, including cancer. Progress in un- Breast cancer, which is the most prevalent malignancy derstanding of the functions of PTKs in cancer has result- in women, is a heterogeneous disease that can be catego- ed in the development of novel therapeutics that target rized into five subtypes based on expression of particular specific changes in protein tyrosine phosphorylation- markers. They are luminal A and B (which are hormone dependent signaling that drive cancer etiology (Hunter receptor-positive [estrogen and progesterone receptors]), 2009; Sliwkowski and Mellman 2013). In contrast, the therapeutic potential of the PTPs has yet to be exploited © 2017 Zhang et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publica- tion date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six Corresponding author: [email protected] months, it is available under a Creative Commons License (Attribution-Non- Article published online ahead of print. Article and publication date are Commercial 4.0 International), as described at http://creativecommons.org/ online at http://www.genesdev.org/cgi/doi/10.1101/gad.304261.117. licenses/by-nc/4.0/. GENES & DEVELOPMENT 31:1–19 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/17; www.genesdev.org 1 Downloaded from genesdev.cshlp.org on November 3, 2017 - Published by Cold Spring Harbor Laboratory Press Zhang et al. HER2-positive (which are defined by high levels of the tumorigenesis. It was reported that deletion of PTPN12 HER2 PTK and are hormone receptor-negative), triple- in human and mouse breast tumor cells decreased tumor- negative (which is both HER2-negative and hormone igenic and metastatic potential in vivo, consistent with receptor-negative and has also been classified as basal- PTPN12 itself being a therapeutic target in certain con- like), and normal-like (which is similar to luminal cancer, texts (Harris et al. 2014). being hormone receptor-positive but HER2-negative). In this study, we focused on PTPN23, which is a ubiqui- Currently, prognosis and therapeutic strategy vary for tously expressed classical PTP composed of five domains each subtype. A variety of drugs that target HER2 have (Gingras et al. 2009a; Bissig and Gruenberg 2014). The been developed, including antibodies such as herceptin/ BRO1-like and V domains are important in ESCRT (endo- trastuzumab, antibody conjugates such as T-DM1/ somal sorting complexes required for transport) sorting of Kadcyla, and small-molecule drugs such as lapatinib. several cell surface receptors, such as EGFR and integrin Although these target the cancer cell with specificity, (Ali et al. 2013; Kharitidi et al. 2015). The gene encoding there remain problems of resistance, both intrinsic and ac- PTPN23 resides on chromosome 3p21, a region that is quired, that limit the effectiveness of such therapies. In frequently homozygously or hemizygously deleted in contrast, triple-negative breast cancer (TNBC), which is various human tumors, also consistent with a tumor- aggressive and characterized by poor prognosis (Rakha suppressive function (Senchenko et al. 2004; Angeloni et al. 2008), is treated with combinations of surgery, radi- 2007). The observation that the catalytic activity of ation, and chemotherapies. It has been reported that there PTP-TD14 (the rat PTPN23 ortholog) is required to sup- are distinct tyrosine phosphorylation-dependent signa- press RAS-mediated transformation of fibroblasts in soft tures associated with basal breast cancer cells, in particu- agar assay (Cao et al. 1998) emphasized the importance lar featuring the SRC family of PTKs (Hochgrafe et al. of the C-terminal catalytic domain in its tumor suppres- 2010). Nevertheless, these remain to be exploited for sor function. In addition, suppression of PTPN23 has targeted therapy, and further insights into the signaling also been implicated in miR-142-3p-mediated increases changes associated with the various breast cancer sub- in soft agar colony formation by a human testicular types are required. germ cell tumor cell line, whereas overexpression of In order to understand the potential therapeutic signifi- PTPN23 impedes xenograft growth of testicular germ cance of any alterations in tyrosine phosphorylation asso- cell tumors in vivo (Tanaka et al. 2013). Furthermore, ciated with breast cancer, it is essential to establish the in a transgenic mouse study, hemizygous deletion of contribution of both PTKs and PTPs to such changes. PTPN23 results in sporadic lung adenoma and B-cell lym- Some progress has been made characterizing the function phoma and promotes the establishment and progression of particular PTPs in breast cancer models. Considering of Myc-driven lymphoma (Manteghi et al. 2016). In the the conventional oncogenic function of PTKs and prompt- same study, it was reported that loss of PTPN23 in pa- ed by their opposing enzymatic function, the PTPs have tients coincided with poor survival (Manteghi et al. 2016). commonly been considered tumor-suppressive. Studies Our laboratory performed RNAi-mediated loss-of-func- in cell and animal models have implicated PTPRE, PTPRJ, tion screens to test the effects of suppressing systemati- and PTPN13 in the development of breast cancer (Freiss cally the expression of PTP family members in three- and Vignon 2004). The expression of PTPRG is down-reg- dimensional cell culture models. We identified several ulated in breast tumors (Zheng et al. 2000). In mechanistic PTPs as novel negative and positive regulators of HER2 studies, PTPRO (Yu et al. 2012), PTPN9 (Yuan et al. 2010), signaling in the control of cell polarity, migration, and in- and PTPN13 (Zhu et al. 2008) have been shown to antag- vasion (Lin et al. 2011; Ramesh et al. 2015). Interestingly, onize HER2 signaling via direct dephosphorylation in sev- only PTPN23 was shown to inhibit mammary epithelial eral models of mammary carcinogenesis. Nevertheless, cell motility and invasion in a HER2-independent manner
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