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  • Original Paper
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Expression of protein tyrosine phosphatase alpha (RPTPα) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo

Abstract

Tyrosine phosphorylation is controlled by a balance of tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Whereas the contribution of PTKs to breast tumorigenesis is the subject of intense scrutiny, the potential role of PTPs is poorly known. RPTPα is implicated in the activation of Src family kinases, and regulation of integrin signaling, cell adhesion, and growth factor responsiveness. To explore its potential contribution to human neoplasia, we surveyed RPTPα protein levels in primary human breast cancer. We found RPTPα levels to vary widely among tumors, with 29% of cases manifesting significant overexpression. High RPTPα protein levels correlated significantly with low tumor grade and positive estrogen receptor status. Expression of RPTPα in breast carcinoma cells led to growth inhibition, associated with increased accumulation in G0 and G1, and delayed tumor growth and metastasis. To our knowledge, this is the first example of a study correlating expression level of a specific bona fide PTP with neoplastic disease status in humans.

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Abbreviations

PTK:

protein tyrosine kinase

PTP:

protein tyrosine phosphatase

RTK:

receptor tyrosine kinase

SFK:

Src family kinase

References

  • Aicher B, Lerch MM, Muller T, Schilling J and Ullrich A. . 1997 J. Cell. Biol. 138: 681–696.

  • Barker KT, Martindale JE, Mitchell PJ, Kamalati T, Page MJ, Phippard DJ, Dale TC, Gusterson BA and Crompton MR. . 1995 Oncogene 10: 569–575.

  • Brondello JM, Brunet A, Pouyssegur J and McKenzie FR. . 1997 J. Biol. Chem. 272: 1368–1376.

  • Carraway III KL and Cantley LC. . 1994 Cell 78: 5–8.

  • Carraway III KL, Rossi EA, Komatsu M, Price-Schiavi SA, Huang D, Guy PM, Carvajal ME, Fregien N, Carraway CA and Carraway KL. . 1999 J. Biol. Chem. 274: 5263–5266.

  • Cartwright CA, Meisler AI and Eckhart W. . 1990 Proc. Natl. Acad. Sci. USA 87: 558–562.

  • Cong L-N, Chen H, Li Y, Lin CH, Sap J and Quon M. . 1999 Biochem. Biophys. Res. Commun. 255: 200–207.

  • Daum G, Regenass S, Sap J, Schlessinger J and Fischer EH. . 1994 J. Biol. Chem. 269: 10524–10528.

  • den Hertog J and Hunter T. . 1996 EMBO J. 15: 3016–3027.

  • den Hertog J, Pals CEGM, Peppelenbosch M, Tertoolen LGJ, De Laat SW and Kruijer W. . 1993 EMBO J. 12: 3789–3798.

  • den Hertog J, Tracy S and Hunter T. . 1994 EMBO J. 13: 3020–3032.

  • Di Fiore PP, Pierce JH, Kraus MH, Segatto O, King CR and Aaronson SA. . 1987 Science 237: 178–182.

  • Egan C, Pang A, Durda D, Cheng HC, Wang JH and Fujita DJ. . 1999 Oncogene 18: 1227–1237.

  • Ellis MJ, Jenkins S, Hanfelt J, Redington ME, Taylor M, Leek R, Siddle K and Harris A. . 1998 Breast Cancer Res. Treat. 52: 175–184.

  • Elson A. . 1999 Oncogene 18: 7535–7542.

  • Elson A and Leder P. . 1995a Proc. Natl. Acad. Sci. USA 92: 12335–12339.

  • Elson A and Leder P. . 1995b J. Biol. Chem. 270: 26116–26122.

  • Elston CW. . 1984 Australian New Zealand J. Surg. 54: 11–15.

  • Feng GS. . 1999 Exp. Cell. Res. 253: 47–54.

  • Fischer EH, Charbonneau H and Tonks NK. . 1991 Science 253: 401–406.

  • Freiss G and Vignon F. . 1994 Mol. Endocrinol. 8: 1389–1396.

  • Ghoussoub RA, Dillon DA, D’Aquila T, Rimm EB, Fearon ER and Rimm DL. . 1998 Cancer 82: 1513–1520.

  • Giani C, Casalini P, Pupa SM, De Vecchi R, Ardini E, Colnaghi MI, Giordano A and Menard S. . 1998 Oncogene 17: 425–432.

  • Irby RB, Mao W, Coppola D, Kang J, Loubeau JM, Trudeau W, Karl R, Fujita DJ, Jove R and Yeatman TJ. . 1999 Nat. Genet. 21: 187–190.

  • Jacob KK, Sap J and Stanley FM. . 1998 J. Biol. Chem. 273: 4800–4809.

  • Kaplan R, Morse B, Huebner K, Croce C, Howk R, Ravera M, Ricca G, Jaye M and Schlessinger J. . 1990 Proc. Natl. Acad. Sci. USA 87: 7000–7004.

  • Keane MM, Lowrey GA, Ettenberg SA, Dayton MA and Lipkowitz S. . 1996 Cancer Res. 56: 4236–4243.

  • Kharitonenkov A, Chen Z, Sures I, Wang H, Schilling J and Ullrich A. . 1997 Nature 386: 181–186.

  • Lee RJ, Albanese C, Stenger RJ, Watanabe G, Inghirami G, Haines III GK, Webster M, Muller WJ, Brugge JS, Davis RJ and Pestell RG. . 1999 J. Biol. Chem. 274: 7341–7350.

  • Lollini P-G, Nicoletti G, Landuzzi L, De Giovanni C, Rossi I, Di Carlo E, Musiani P, Muller WJ and Nanni P. . 1998 Int. J. Cancer 77: 937–941.

  • Maa M-C, Leu T-H, McCarley DJ, Schatzman RC and Parsons SJ. . 1995 Proc. Natl. Acad. Sci. USA 92: 6981–6985.

  • Maehama T and Dixon JE. . 1999 Trends Cell. Biol. 9: 125–128.

  • Maggiora P, Marchio S, Stella MC, Giai M, Belfiore A, De Bortoli M, Di Renzo MF, Costantino A, Sismondi P and Comoglio PM. . 1998 Oncogene 16: 2927–2933.

  • McCarty Jr KS, Miller LS, Cox EB, Konrath J and McCarty KS. . 1985 Arch. Pathol. Lab. Med. 109: 716–721.

  • Moller NP, Moller KB, Lammers R, Kharitonenkov A, Hoppe E, Wiberg FC, Sures I and Ullrich A. . 1995 J. Biol. Chem. 270: 23126–23131.

  • Muthuswamy SK, Siegel PM, Dankort DL, Webster MA and Muller WJ. . 1994 Mol. Cell. Biol. 14: 735–743.

  • Neel BG. . 1997 Curr. Opin. Immunol. 9: 405–420.

  • Neel BG and Tonks NK. . 1997 Curr. Opin. Cell. Biol. 9: 193–204.

  • Ostman A, Yang Q and Tonks NK. . 1994 Proc. Natl. Acad. Sci. USA 91: 9680–9684.

  • Ottenhoff-Kalff AE, Rijksen G, Van Beurden EACM, Hennipman A, Michels AA and Staal GEJ. . 1992 Cancer Res. 52: 4773–4778.

  • Ottenhoff-Kalff AE, van Oirschot BA, Hennipman A, de Weger RA, Staal GE and Rijksen G. . 1995 Breast Cancer Res. Treat. 33: 245–256.

  • Pereira H, Pinder SE, Sibbering DM, Galea MH, Elston CW, Blamey RW, Robertson JFR and Ellis IO. . 1995 Histopathology 27: 219–226.

  • Petrone A and Sap J. . 2000 J. Cell. Sci. 113: 2345–2354.

  • Pizao PE, Lyarun DM, Peters GP, van Ark-Otte J, Winograd B, Giaccone G and Pinedo HM. . 1992 Br. J. Cancer 66: 660–665.

  • Ponniah S, Wang DZ, Lim KL and Pallen CJ. . 1999 Curr. Biol. 9: 535–538.

  • Porter AC and Vaillancourt RR. . 1998 Oncogene 17: 1343–1352.

  • Rosenkranz S, Ikuno Y, Leong FL, Klinghoffer RA, Miyake S, Band H and Kazlauskas A. . 2000 J. Biol. Chem. 275: 9620–9627.

  • Ross JS and Fletcher JA. . 1999 Semin. Cancer Biol. 9: 125–138.

  • Schwartzberg PL. . 1998 Oncogene 17: 1463–1468.

  • Sell C, Dumenil G, Deveaud C, Miura M, Coppola D, DeAngelis T, Rubin R, Efstratiadis A and Baserga R. . 1994 Mol. Cell. Biol. 14: 3604–3612.

  • Silvestrini R, Daidone MG and Gasparini G. . 1985 Cancer 56: 1982–1987.

  • Su J, Muranjan M and Sap J. . 1999 Curr. Biol. 9: 505–511.

  • Su J, Yang L-T and Sap J. . 1996 J. Biol. Chem. 271: 28026–28096.

  • Sun H, Charles CH, Lau LF and Tonks NK. . 1993 Cell 75: 487–493.

  • Tabiti K, Smith DR, Goh H-S and Pallen CJ. . 1995 Cancer Lett. 93: 239–248.

  • Tice DA, Biscardi JS, Nickles AL and Parsons SJ. . 1999 Proc. Natl. Acad. Sci. USA 96: 1415–1420.

  • Tzahar E and Yarden Y. . 1998 Biochim. Biophys. Acta 1377: M25–M37.

  • UICC. (1997). . Illustrated guide to the TNM/pTNM classification of malignant tumours, 4th edn. Springer-Verlag.

  • Werner H and Le Roith D. . 1997 Crit. Rev. Oncog. 8: 71–92.

  • Zhai Y, Wirth J, Kang S, Welsh CW and Esselman WJ. . 1995 Mol. Carcinogen. 14: 103–110.

  • Zhai Y-F, Beittenmiller H, Wang B, Gould MN, Oakley C, Esselman WJ and Welsch CW. . 1993 Cancer Res. 53: 2272–2278.

  • Zheng XM, Resnick RJ and Shalloway D. . 2000 EMBO J. 19: 964–978.

  • Zheng XM, Wang Y and Pallen CJ. . 1992 Nature 359: 336–339.

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Acknowledgements

Supported by NIH (R29 CA68365 to J Sap; NCI core support grant P30CA16087), U.S. Department of Defense (DAMD17-98-1-8136 to J Sap), and Associazione Italiana per la Ricerca sul Cancro (to E Ardini and S Ménard). J Sap is the recipient of an Irma T Hirschl career scientist award. Work was initiated through a pilot project under NIH breast cancer program development grant 5R21 CA66229-04. We appreciated comments on the manuscript by Drs G Inghirami, J Melamed, A Pellicer and F Symmans. We thank Dr P Lollini for N202.1A cells, F Castiglioni for help with figures, and C Ghirelli for technical assistance.

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Ardini, E., Agresti, R., Tagliabue, E. et al. Expression of protein tyrosine phosphatase alpha (RPTPα) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo. Oncogene 19, 4979–4987 (2000). https://doi.org/10.1038/sj.onc.1203869

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