Journal of Cancer Research and Clinical Oncology

, Volume 139, Issue 7, pp 1129–1139 | Cite as

Protein tyrosine phosphatase kappa (PTPRK) is a negative regulator of adhesion and invasion of breast cancer cells, and associates with poor prognosis of breast cancer

  • Ping-Hui SunEmail author
  • Lin Ye
  • Malcolm D. Mason
  • Wen G. Jiang
Original Paper



Receptor-like protein tyrosine phosphatase kappa (PTPRK) has been shown to exhibit homophilic binding. It is a putative tumour suppressor in primary central nervous system lymphomas and colorectal cancer. The present study investigated the expression of PTPRK in breast cancer and the biological impact of PTPRK on breast cancer cells.


Expression of PTPRK protein and gene transcript was examined in a cohort of breast cancer patients. The association of PTPRK transcript level and pathological and clinical aspects was then analysed. Knockdown of PTPRK in breast cancer cells was performed using a specific anti-PTPRK transgene. The impact of PTPRK knockdown on breast cancer cells was investigated using in vitro cell function assays.


Lower levels of PTPRK transcripts were seen in the advanced breast cancer. The reduced PTPRK transcript levels were associated with poor prognosis of the disease. PTPRK transcript levels were decreased in the primary tumours of patients who died from breast cancer or had metastases. Patients with lower expression of PTPRK had shorter survival compared with those higher expression levels of PTPRK. Knockdown of PTPRK resulted in increased proliferation, adhesion, invasion, and migration of breast cancer cells in vitro.


Decreased expression of PTPRK in breast cancer is correlated with poor prognosis. PTPRK is a negative regulator of adhesion, invasion, migration, and proliferation of breast cancer cells. This suggests that PTPRK is a potential tumour suppressor in breast cancer.


PTPRK Breast cancer Prognosis 



RAC-alpha serine/threonine-protein kinase


Cell adhesion molecule


Epidermal growth factor receptor


Extracellular signal regulated kinase


c-Jun N-terminal kinase


Nottingham Prognostic Index


Nuclear factor kappa B


Phosphoinositide 3-kinase


Protein kinase C


Phospholipase Cγ1


Protein tyrosine kinase


Protein tyrosine phosphatase


Receptor-like protein tyrosine phosphatase



The authors would thank the support from Cancer Research Wales and Breast Cancer Hope Foundation.

Conflict of interest

The authors declare that they have no competing interests.


  1. Angers-Loustau A, Cote JF, Tremblay ML (1999) Roles of protein tyrosine phosphatases in cell migration and adhesion. Biochem Cell Biol 77(6):493–505PubMedCrossRefGoogle Scholar
  2. Ardini E, Agresti R, Tagliabue E, Greco M, Aiello P, Yang LT, Menard S, Sap J (2000) Expression of protein tyrosine phosphatase alpha (RPTPalpha) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo. Oncogene 19(43):4979–4987PubMedCrossRefGoogle Scholar
  3. Bjorge JD, Pang A, Fujita DJ (2000) Identification of protein-tyrosine phosphatase 1B as the major tyrosine phosphatase activity capable of dephosphorylating and activating c-Src in several human breast cancer cell lines. J Biol Chem 275(52):41439–41446PubMedCrossRefGoogle Scholar
  4. Giefing M, Zemke N, Brauze D, Kostrzewska-Poczekaj M, Luczak M, Szaumkessel M, Pelinska K, Kiwerska K, Tonnies H, Grenman R, Figlerowicz M, Siebert R, Szyfter K, Jarmuz M (2011) High resolution ArrayCGH and expression profiling identifies PTPRD and PCDH17/PCH68 as tumor suppressor gene candidates in laryngeal squamous cell carcinoma. Genes Chromosomes Cancer 50(3):154–166PubMedCrossRefGoogle Scholar
  5. Gyorffy B, Dietel M, Fekete T, Lage H (2008) A snapshot of microarray-generated gene expression signatures associated with ovarian carcinoma Int J Gynecol Cancer 18(6):1215–1233Google Scholar
  6. Jiang WG, Hiscox S, Hallett MB, Horrobin DF, Mansel RE, Puntis MC (1995) Regulation of the expression of E-cadherin on human cancer cells by gamma-linolenic acid (GLA). Cancer Res 55(21):5043–5048PubMedGoogle Scholar
  7. Jiang WG, Hiscox SE, Parr C, Martin TA, Matsumoto K, Nakamura T, Mansel RE (1999) Antagonistic effect of NK4, a novel hepatocyte growth factor variant, on in vitro angiogenesis of human vascular endothelial cells. Clin Cancer Res 5(11):3695–3703PubMedGoogle Scholar
  8. Jiang WG, Watkins G, Fodstad O, Douglas-Jones A, Mokbel K, Mansel RE (2004) Differential expression of the CCN family members Cyr61 CTGF and Nov in human breast cancer. Endocr Relat Cancer 11(4):781–791PubMedCrossRefGoogle Scholar
  9. Jiang WG, Davies G, Martin TA, Parr C, Watkins G, Mason MD, Mokbel K, Mansel RE (2005) Targeting matrilysin and its impact on tumor growth in vivo: the potential implications in breast cancer therapy. Clin Cancer Res 11(16):6012–6019PubMedCrossRefGoogle Scholar
  10. Keane MM, Lowrey GA, Ettenberg SA, Dayton MA, Lipkowitz S (1996) The protein tyrosine phosphatase DEP-1 is induced during differentiation and inhibits growth of breast cancer cells. Cancer Res 56(18):4236–4243PubMedGoogle Scholar
  11. Konishi N, Tsujikawa K, Yamamoto H, Ishida E, Nakamura M, Shimada K, Yane K, Yamashita H, Noguchi S (2003) Overexpression of leucocyte common antigen (LAR) P-subunit in thyroid carcinomas. Br J Cancer 88(8):1223–1228PubMedCrossRefGoogle Scholar
  12. Kulas DT, Goldstein BJ, Mooney RA (1996) The transmembrane protein-tyrosine phosphatase LAR modulates signaling by multiple receptor tyrosine kinases. J Biol Chem 271(2):748–754PubMedCrossRefGoogle Scholar
  13. LaForgia S, Morse B, Levy J, Barnea G, Cannizzaro LA, Li F, Nowell PC, Boghosian-Sell L, Glick J, Weston A et al (1991) Receptor protein-tyrosine phosphatase gamma is a candidate tumor suppressor gene at human chromosome region 3p21. Proc Natl Acad Sci USA 88(11):5036–5040PubMedCrossRefGoogle Scholar
  14. Liu S, Sugimoto Y, Kulp SK, Jiang J, Chang HL, Park KY, Kashida Y, Lin YC (2002) Estrogenic down-regulation of protein tyrosine phosphatase gamma (PTP gamma) in human breast is associated with estrogen receptor alpha. Anticancer Res 22(6C):3917–3923PubMedGoogle Scholar
  15. Motiwala T, Ghoshal K, Das A, Majumder S, Weichenhan D, Wu YZ, Holman K, James SJ, Jacob ST, Plass C (2003) Suppression of the protein tyrosine phosphatase receptor type O gene (PTPRO) by methylation in hepatocellular carcinomas. Oncogene 22(41):6319–6331PubMedCrossRefGoogle Scholar
  16. Motiwala T, Kutay H, Ghoshal K, Bai S, Seimiya H, Tsuruo T, Suster S, Morrison C, Jacob ST (2004) Protein tyrosine phosphatase receptor-type O (PTPRO) exhibits characteristics of a candidate tumor suppressor in human lung cancer. Proc Natl Acad Sci USA 101(38):13844–13849PubMedCrossRefGoogle Scholar
  17. Nakamura M, Kishi M, Sakaki T, Hashimoto H, Nakase H, Shimada K, Ishida E, Konishi N (2003) Novel tumor suppressor loci on 6q22-23 in primary central nervous system lymphomas. Cancer Res 63(4):737–741PubMedGoogle Scholar
  18. Novellino L, De Filippo A, Deho P, Perrone F, Pilotti S, Parmiani G, Castelli C (2008) PTPRK negatively regulates transcriptional activity of wild type and mutated oncogenic beta-catenin and affects membrane distribution of beta-catenin/E-cadherin complexes in cancer cells. Cell Signal 20(5):872–883PubMedCrossRefGoogle Scholar
  19. Ponniah S, Wang DZ, Lim KL, Pallen CJ (1999) Targeted disruption of the tyrosine phosphatase PTPalpha leads to constitutive downregulation of the kinases Src and Fyn. Curr Biol 9(10):535–538PubMedCrossRefGoogle Scholar
  20. Sap J, Jiang YP, Friedlander D, Grumet M, Schlessinger J (1994) Receptor tyrosine phosphatase R-PTP-kappa mediates homophilic binding. Mol Cell Biol 14(1):1–9PubMedGoogle Scholar
  21. Starr TK, Allaei R, Silverstein KA, Staggs RA, Sarver AL, Bergemann TL, Gupta M, O’Sullivan MG, Matise I, Dupuy AJ, Collier LS, Powers S, Oberg AL, Asmann YW, Thibodeau SN, Tessarollo L, Copeland NG, Jenkins NA, Cormier RT, Largaespada DA (2009) A transposon-based genetic screen in mice identifies genes altered in colorectal cancer. Science 323(5922):1747–1750PubMedCrossRefGoogle Scholar
  22. Stoker AW (2005) Protein tyrosine phosphatases and signalling. J Endocrinol 185(1):19–33PubMedCrossRefGoogle Scholar
  23. Su J, Muranjan M, Sap J (1999) Receptor protein tyrosine phosphatase alpha activates Src-family kinases and controls integrin-mediated responses in fibroblasts. Curr Biol 9(10):505–511PubMedCrossRefGoogle Scholar
  24. Tabiti K, Smith DR, Goh HS, Pallen CJ (1995) Increased mRNA expression of the receptor-like protein tyrosine phosphatase alpha in late stage colon carcinomas. Cancer Lett 93(2):239–248PubMedCrossRefGoogle Scholar
  25. Tonks NK (2006) Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol 7(11):833–846PubMedCrossRefGoogle Scholar
  26. Wang Z, Shen D, Parsons DW, Bardelli A, Sager J, Szabo S, Ptak J, Silliman N, Peters BA, van der Heijden MS, Parmigiani G, Yan H, Wang TL, Riggins G, Powell SM, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 304(5674):1164–1166PubMedCrossRefGoogle Scholar
  27. Wang SE, Wu FY, Shin I, Qu S, Arteaga CL (2005) Transforming growth factor beta (TGF-{beta})-Smad target gene protein tyrosine phosphatase receptor type kappa is required for TGF-{beta} function. Mol Cell Biol 25(11):4703–4715PubMedCrossRefGoogle Scholar
  28. Wiener JR, Kerns BJ, Harvey EL, Conaway MR, Iglehart JD, Berchuck A, Bast RC Jr (1994) Overexpression of the protein tyrosine phosphatase PTP1B in human breast cancer: association with p185c-erbB-2 protein expression. J Natl Cancer Inst 86(5):372–378PubMedCrossRefGoogle Scholar
  29. Xu Y, Tan LJ, Grachtchouk V, Voorhees JJ, Fisher GJ (2005) Receptor-type protein-tyrosine phosphatase-kappa regulates epidermal growth factor receptor function. J Biol Chem 280(52):42694–42700PubMedCrossRefGoogle Scholar
  30. Yang Y, Gil M, Byun SM, Choi I, Pyun KH, Ha H (1996) Transforming growth factor-beta1 inhibits human keratinocyte proliferation by upregulation of a receptor-type tyrosine phosphatase R-PTP-kappa gene expression. Biochem Biophys Res Commun 228(3):807–812PubMedCrossRefGoogle Scholar
  31. Yang T, Zhang JS, Massa SM, Han X, Longo FM (1999) Leukocyte common antigen-related tyrosine phosphatase receptor: increased expression and neuronal-type splicing in breast cancer cells and tissue. Mol Carcinog 25(2):139–149PubMedCrossRefGoogle Scholar
  32. Zhai YF, Beittenmiller H, Wang B, Gould MN, Oakley C, Esselman WJ, Welsch CW (1993) Increased expression of specific protein tyrosine phosphatases in human breast epithelial cells neoplastically transformed by the neu oncogene. Cancer Res 53(10 Suppl):2272–2278PubMedGoogle Scholar
  33. Zheng XM, Wang Y, Pallen CJ (1992) Cell transformation and activation of pp 60c-src by overexpression of a protein tyrosine phosphatase. Nature 359(6393):336–339PubMedCrossRefGoogle Scholar
  34. Zheng J, Kulp SK, Zhang Y, Sugimoto Y, Dayton MA, Govindan MV, Brueggemeier RW, Lin YC (2000) 17 beta-estradiol-regulated expression of protein tyrosine phosphatase gamma gene in cultured human normal breast and breast cancer cells. Anticancer Res 20(1A):11–19PubMedGoogle Scholar
  35. Zondag GC, Koningstein GM, Jiang YP, Sap J, Moolenaar WH, Gebbink MF (1995) Homophilic interactions mediated by receptor tyrosine phosphatases mu and kappa. A critical role for the novel extracellular MAM domain. J Biol Chem 270(24):14247–14250PubMedCrossRefGoogle Scholar
  36. Zuker M (2003) Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31(13):3406–3415PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Ping-Hui Sun
    • 1
    Email author
  • Lin Ye
    • 1
  • Malcolm D. Mason
    • 1
  • Wen G. Jiang
    • 1
  1. 1.Metastasis and Angiogenesis Research Group, Institute of Cancer and GeneticsCardiff University School of MedicineCardiffUK

Personalised recommendations