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Altered expression of p120catenin predicts poor outcome in invasive breast cancer

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Abstract

Purpose

The study focuses on p120catenin, a regulator of cell adhesion, which has previously been described in many malignancies and suggested with a role in invasion and metastatic behaviour. In this study, we investigate the role of altered immunoexpression of p120catenin isoforms in the prognosis of invasive breast cancer (n = 351).

Methods

We used cDNA microarrays to screen differences in gene expression in invasive breast cancer in general, and between local and metastasized disease particularly. On this basis, we performed p120catenin immunohistochemistry in order to confirm the prognostic value of p120catenin isoforms on tissue microarrays comprising 341 patients from the era of mammographic screening, directed to modern surgical and oncological treatments, and followed-up for maximum of 20 years.

Results

In cDNA microarray analysis, p120catenin was discovered down-regulated along with E-cadherin and α-catenin. In addition, p120catenin distinguished metastasized breast cancer from local disease. Immunohistochemistry confirmed the value of p120catenin as an independent prognosticator of breast cancer survival. In our results, p120catenin was associated with 3.7-fold risk of breast cancer death in multivariate Cox’s regression analyses adjusted for the established prognosticators of breast cancer (p = 0.039). Particularly, the long isoform of p120catenin predicted metastatic disease (p = 0.029).

Conclusion

The present paper is the first report on p120catenin in invasive breast cancer based on a well-characterized patient material with long-term follow-up. We observed altered expression of p120catenin isoforms in invasive breast cancer and, in our material, the decrease in p120 immunoexpression was significantly associated with poor outcome of disease.

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References

  • Aho S, Levänsuo L, Montonen O, Kari C, Rodeck U, Uitto J (2002) Specific sequences in p120ctn determine subcellular distribution of its multiple isoforms involved in cellular adhesion of normal and malignant epithelial cells. J Cell Sci 115:1391–1402

    CAS  PubMed  Google Scholar 

  • Bellovin DI, Bates RC, Muzikansky A, Rimm DL, Mercurio AM (2005) Altered localization of p120 catenin during epithelial to mesenchymal transition of colon carcinoma is prognostic for aggressive disease. Cancer Res 65:10938–10945

    Article  CAS  PubMed  Google Scholar 

  • Berx G, Cleton-Jansen AM, Strumane K, de Leeuw WJ, Nollet F, van Roy F, Cornelisse C (1996) E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene 13:1919–1925

    CAS  PubMed  Google Scholar 

  • Bukholm IK, Nesland JM, Kåresen R, Jacobsen U, Børresen-Dale AL (1998) E-cadherin and alpha-, beta-, and gamma-catenin protein expression in relation to metastasis in human breast carcinoma. J Pathol 185:262–266

    Article  CAS  PubMed  Google Scholar 

  • Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295:2492–2502

    Article  CAS  PubMed  Google Scholar 

  • Chung Y, Lam AK, Luk JM, Law S, Chan KW, Lee PY, Wong J (2007) Altered E-cadherin expression and p120 catenin localization in esophageal squamous cell carcinoma. Ann Surg Oncol 14:3260–3267

    Article  PubMed  Google Scholar 

  • Corsino PE, Davis BJ, Nørgaard PH, Parker NN, Law M, Dunn W, Law BK (2008) Mammary tumors initiated by constitutive Cdk2 activation contain an invasive basal-like component. Neoplasia 10:1240–1252

    CAS  PubMed  Google Scholar 

  • Da Silva L, Parry S, Reid L, Keith P, Waddell N, Kossai M, Clarke C, Lakhani SR, Simpson PT (2008) Aberrant expression of E-cadherin in lobular carcinomas of the breast. Am J Surg Pathol 32:773–783

    Article  PubMed  Google Scholar 

  • Dabbs DJ, Bhargava R, Chivukula M (2007a) Lobular versus ductal breast neoplasms: the diagnostic utility of p120 catenin. Am J Surg Pathol 31:427–437

    Article  PubMed  Google Scholar 

  • Dabbs DJ, Kaplai M, Chivukula M, Kanbour A, Kanbour-Shakir A, Carter GJ (2007b) The spectrum of morphomolecular abnormalities of the E-cadherin/catenin complex in pleomorphic lobular carcinoma of the breast. Appl Immunohistochem Mol Morphol 15:260–266

    Article  CAS  PubMed  Google Scholar 

  • Daniel JM, Reynolds AB (1999) The catenin p120(ctn) interacts with Kaiso, a novel BTB/POZ domain zinc finger transcription factor. Mol Cell Biol 19:3614–3623

    CAS  PubMed  Google Scholar 

  • Daniel JM, Spring CM, Crawford HC, Reynolds AB, Baig A (2002) The p120(ctn)-binding partner Kaiso is a bi-modal DNA-binding protein that recognizes both a sequence-specific consensus and methylated CpG dinucleotides. Nucleic Acids Res 30:2911–2919

    Article  CAS  PubMed  Google Scholar 

  • Davis MA, Ireton RC, Reynolds AB (2003) A core function for p120-catenin in cadherin turnover. J Cell Biol 163:525–534

    Article  CAS  PubMed  Google Scholar 

  • De Leeuw WJ, Berx G, Vos CB, Peterse JL, Van de Vijver MJ, Litvinov S, Van Roy F, Cornelisse CJ, Cleton-Jansen AM (1997) Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ. J Pathol 183:404–411

    Article  PubMed  Google Scholar 

  • Esposito NN, Chivukula M, Dabbs DJ (2007) The ductal phenotypic expression of the E-cadherin/catenin complex in tubulolobular carcinoma of the breast: an immunohistochemical and clinicopathologic study. Mod Pathol 20:130–138

    Article  CAS  PubMed  Google Scholar 

  • Fisher ER, Anderson S, Dean S, Dabbs D, Fisher B, Siderits R, Pritchard J, Pereira T, Geyer C, Wolmark N (2005) Solving the dilemma of the immunohistochemical and other methods used for scoring estrogen receptor and progesterone receptor in patients with invasive breast carcinoma. Cancer 103:164–173

    Article  CAS  PubMed  Google Scholar 

  • Gold JS, Reynolds AB, Rimm DL (1998) Loss of p120ctn in human colorectal cancer predicts metastasis and poor survival. Cancer Lett 132:193–201

    Article  CAS  PubMed  Google Scholar 

  • Gould Rothberg BE, Bracken MB (2006) E-cadherin immunohistochemical expression as a prognostic factor in infiltrating ductal carcinoma of the breast: a systematic review and meta-analysis. Breast Cancer Res Treat 100:139–148

    Article  CAS  PubMed  Google Scholar 

  • Grosheva I, Shtutman M, Elbaum M, Bershadsky AD (2001) p120 catenin affects cell motility via modulation of activity of Rho-family GTPases: a link between cell–cell contact formation and regulation of cell locomotion. J Cell Sci 114:695–707

    CAS  PubMed  Google Scholar 

  • Husmark J, Heldin NE, Nilsson M (1999) N-cadherin-mediated adhesion and aberrant catenin expression in anaplastic thyroid-carcinoma cell lines. Int J Cancer 83:692–699

    Article  CAS  PubMed  Google Scholar 

  • Ireton RC, Davis MA, van Hengel J, Mariner DJ, Barnes K, Thoreson MA, Anastasiadis PZ, Matrisian L, Bundy LM, Sealy L, Gilbert B, van Roy F, Reynolds AB (2002) A novel role for p120 catenin in E-cadherin function. J Cell Biol 159:465–476

    Article  CAS  PubMed  Google Scholar 

  • Ishizaki Y, Omori Y, Momiyama M, Nishikawa Y, Tokairin T, Manabe M, Enomoto K (2004) Reduced expression and aberrant localization of p120catenin in human squamous cell carcinoma of the skin. J Dermatol Sci 34:99–108

    Article  CAS  PubMed  Google Scholar 

  • Karayiannakis AJ, Nakopoulou L, Gakiopoulou H, Keramopoulos A, Davaris PS, Pignatelli M (2001) Expression patterns of beta-catenin in in situ and invasive breast cancer. Eur J Surg Oncol 27:31–36

    Article  CAS  PubMed  Google Scholar 

  • Keirsebilck A, Bonné S, Staes K, van Hengel J, Nollet F, Reynolds A, van Roy F (1998) Molecular cloning of the human p120ctn catenin gene (CTNND1): expression of multiple alternatively spliced isoforms. Genomics 50:129–146

    Article  CAS  PubMed  Google Scholar 

  • Kelly KF, Spring CM, Otchere AA, Daniel JM (2004) NLS-dependent nuclear localization of p120ctn is necessary to relieve Kaiso-mediated transcriptional repression. J Cell Sci 117:2675–2686

    Article  CAS  PubMed  Google Scholar 

  • Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847

    Article  CAS  PubMed  Google Scholar 

  • Liapis G, Mylona E, Alexandrou P, Giannopoulou I, Nikolaou I, Markaki S, Keramopoulos A, Nakopoulou L (2007) Effect of the different phosphorylated Smad2 protein localizations on the invasive breast carcinoma phenotype. APMIS 115:104–114

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Xu HT, Dai SD, Wei Q, Yuan XM, Wang EH (2007) Reduction of p120(ctn) isoforms 1 and 3 is significantly associated with metastatic progression of human lung cancer. APMIS 115:848–856

    Article  CAS  PubMed  Google Scholar 

  • Lo Muzio L, Pannone G, Staibano S, Mignogna MD, Serpico R, Fanali S, De Rosa G, Piattelli A, Mariggiò MA (2002) p120(cat) Delocalization in cell lines of oral cancer. Oral Oncol 38:64–72

    Article  CAS  PubMed  Google Scholar 

  • Mastracci TL, Tjan S, Bane AL, O’Malley FP, Andrulis IL (2005) E-cadherin alterations in atypical lobular hyperplasia and lobular carcinoma in situ of the breast. Mod Pathol 18:741–751

    Article  CAS  PubMed  Google Scholar 

  • Mayerle J, Friess H, Büchler MW, Schnekenburger J, Weiss FU, Zimmer KP, Domschke W, Lerch MM (2003) Up-regulation, nuclear import, and tumor growth stimulation of the adhesion protein p120 in pancreatic cancer. Gastroenterology 124:949–960

    Article  CAS  PubMed  Google Scholar 

  • Mo YY, Reynolds AB (1996) Identification of murine p120 isoforms and heterogeneous expression of p120cas isoforms in human tumor cell lines. Cancer Res 56:2633–2640

    CAS  PubMed  Google Scholar 

  • Nakopoulou L, Gakiopoulou-Givalou H, Karayiannakis AJ, Giannopoulou I, Keramopoulos A, Davaris P, Pignatelli M (2002) Abnormal alpha-catenin expression in invasive breast cancer correlates with poor patient survival. Histopathology 40:536–546

    Article  CAS  PubMed  Google Scholar 

  • Paredes J, Correia AL, Ribeiro AS, Schmitt F (2007) Expression of p120-catenin isoforms correlates with genomic and transcriptional phenotype of breast cancer cell lines. Cell Oncol 29:467–476

    CAS  PubMed  Google Scholar 

  • Paredes J, Correia AL, Ribeiro AS, Milanezi F, Cameselle-Teijeiro J, Schmitt FC (2008) Breast carcinomas that co-express E- ja P-cadherin are associated with p120-catenin cytoplasmic localisation and poor patient survival. J Clin Pathol 61:856–862

    Article  CAS  PubMed  Google Scholar 

  • Prokhortchouk A, Hendrich B, Jørgensen H, Ruzov A, Wilm M, Georgiev G, Bird A, Prokhortchouk E (2001) The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor. Genes Dev 15:1613–1618

    Article  CAS  PubMed  Google Scholar 

  • Rakha EA, Abd El Rehim D, Pinder SE, Lewis SA, Ellis IO (2005) E-cadherin expression in invasive non-lobular carcinoma of the breast and its prognostic significance. Histopathology 46:685–693

    Article  CAS  PubMed  Google Scholar 

  • Reynolds AB, Roesel DJ, Kanner SB, Parsons JT (1989) Transformation-specific tyrosine phosphorylation of a novel cellular protein in chicken cells expressing oncogenic variants of the avian cellular src gene. Mol Cell Biol 9:629–638

    CAS  PubMed  Google Scholar 

  • Reynolds AB, Herbert L, Cleveland JL, Berg ST, Gaut JR (1992) p120, a novel substrate of protein tyrosine kinase receptors and of p60v-src, is related to cadherin-binding factors beta-catenin, plakoglobin and armadillo. Oncogene 7:2439–2445

    CAS  PubMed  Google Scholar 

  • Roura S, Domínguez D (2004) Inducible expression of p120Cas1B isoform corroborates the role for p120-catenin as a positive regulator of E-cadherin function in intestinal cancer cells. Biochem Biophys Res Commun 320:435–441

    Article  CAS  PubMed  Google Scholar 

  • Sarrió D, Pérez-Mies B, Hardisson D, Moreno-Bueno G, Suárez A, Cano A, Martín-Pérez J, Gamallo C, Palacios J (2004) Cytoplasmic localization of p120ctn and E-cadherin loss characterize lobular breast carcinoma from preinvasive to metastatic lesions. Oncogene 23:3272–3283

    Article  PubMed  Google Scholar 

  • Shibata T, Kokubu A, Sekine S, Kanai Y, Hirohashi S (2004) Cytoplasmic p120ctn regulates the invasive phenotypes of E-cadherin-deficient breast cancer. Am J Pathol 164:2269–2278

    CAS  PubMed  Google Scholar 

  • Silva Neto B, Smith GL, Mandeville JA, Vanni AJ, Wotkowicz C, Rieger-Christ KM, Baumgart E, Jacobs MA, Cohen MS, Zeheb R, Loda M, Libertino JA, Summerhayes IC (2008) Prognostic significance of altered p120 ctn expression in bladder cancer. BJU Int 101:746–752

    Article  PubMed  Google Scholar 

  • Spring CM, Kelly KF, O’Kelly I, Graham M, Crawford HC, Daniel JM (2005) The catenin p120ctn inhibits Kaiso-mediated transcriptional repression of the beta-catenin/TCF target gene matrilysin. Exp Cell Res 305:253–265

    Article  CAS  PubMed  Google Scholar 

  • Stefansson IM, Salvesen HB, Akslen LA (2004) Prognostic impact of alterations in P-cadherin expression and related cell adhesion markers in endometrial cancer. J Clin Oncol 22:1242–1252

    Article  CAS  PubMed  Google Scholar 

  • Tajine M, Elizondo D (2002) New methods for testing linear separability. Neurocomputing 47:161–188

    Article  Google Scholar 

  • Talvinen K, Tuikkala J, Grönroos J, Huhtinen H, Kronqvist P, Aittokallio T, Nevalainen O, Hiekkanen H, Nevalainen T, Sundström J (2006) Biochemical and clinical approaches in evaluating the prognosis of colon cancer. Anticancer Res 26:4745–4751

    CAS  PubMed  Google Scholar 

  • Talvinen K, Tuikkala J, Nevalainen O, Rantanen A, Hirsimäki P, Sundström J, Kronqvist P (2008) Proliferation marker securin identifies favourable outcome in invasive ductal breast cancer. Br J Cancer 99:335–340

    Article  CAS  PubMed  Google Scholar 

  • Tavassoli FA, Devilee P (eds) (2003) World Health Organization Classification of Tumours. Pathology and genetics of tumours of the breast and female genital organs. IARC Press, Lyon, p 19

    Google Scholar 

  • Theodoridis S, Koutroumbas K (2003) Pattern recognition. Academic Press, San Diego

    Google Scholar 

  • Thoreson MA, Reynolds AB (2002) Altered expression of the catenin p120 in human cancer: implications for tumour progression. Differentiation 70:583–589

    Article  CAS  PubMed  Google Scholar 

  • Tran NL, Nagle RB, Cress AE, Heimark RL (1999) N-Cadherin expression in human prostate carcinoma cell lines. An epithelial–mesenchymal transformation mediating adhesion with stromal cells. Am J Pathol 155:787–798

    CAS  PubMed  Google Scholar 

  • Turner BC, Krajewski S, Krajewska M, Takayama S, Gumbs AA, Carter D, Rebbeck TR, Haffty BG, Reed JC (2001) BAG-1: a novel biomarker predicting long-term survival in early-stage breast cancer. J Clin Oncol 19:992–1000

    CAS  PubMed  Google Scholar 

  • van Es JH, Barker N, Clevers H (2003) You Wnt some, you lose some: oncogenes in the Wnt signaling pathway. Curr Opin Genet Dev 13:28–33

    Article  PubMed  Google Scholar 

  • van Hengel J, Vanhoenacker P, Staes K, van Roy F (1999) Nuclear localization of the p120(ctn) Armadillo-like catenin is counteracted by a nuclear export signal and by E-cadherin expression. Proc Natl Acad Sci USA 96:7980–7985

    Article  PubMed  Google Scholar 

  • van Oort IM, Tomita K, van Bokhoven A, Bussemakers MJ, Kiemeney LA, Karthaus HF, Witjes JA, Schalken JA (2007) The prognostic value of E-cadherin and the cadherin-associated molecules alpha-, beta-, gamma-catenin and p120ctn in prostate cancer specific survival: a long-term follow-up study. Prostate 67:1432–1438

    Article  PubMed  Google Scholar 

  • van Roy FM, McCrea PD (2005) A role for Kaiso-p120ctn complexes in cancer? Nat Rev Cancer 5:956–964

    Article  PubMed  Google Scholar 

  • Vos CB, Cleton-Jansen AM, Berx G, de Leeuw WJ, ter Haar NT, van Roy F, Cornelisse CJ, Peterse JL, van de Vijver MJ (1997) E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis. Br J Cancer 76:1131–1133

    CAS  PubMed  Google Scholar 

  • Wang EH, Liu Y, Xu HT, Dai SD, Liu N, Xie CY, Yuan XM (2006) Abnormal expression and clinicopathologic significance of p120-catenin in lung cancer. Histol Histopathol 21:841–847

    PubMed  Google Scholar 

  • Wijnhoven BP, Pignatelli M, Dinjens WN, Tilanus HW (2005) Reduced p120ctn expression correlates with poor survival in patients with adenocarcinoma of the gastroesophageal junction. J Surg Oncol 92:116–123

    Article  CAS  PubMed  Google Scholar 

  • Xie L, Law BK, Aakre ME, Edgerton M, Shyr Y, Bhowmick NA, Moses HL (2003) Transforming growth factor beta-regulated gene expression in a mouse mammary gland epithelial cell line. Breast Cancer Res 5:R187–R198

    Article  CAS  PubMed  Google Scholar 

  • Yanagisawa M, Huveldt D, Kreinest P, Lohse CM, Cheville JC, Parker AS, Copland JA, Anastasiadis PZ (2008) A p120 catenin isoform switch affects Rho activity, induces tumor cell invasion, and predicts metastatic disease. J Biol Chem 283:18344–18354

    Article  CAS  PubMed  Google Scholar 

  • Yang YH, Dudoit S, Luu P, Lin DM, Peng V, Ngai J, Speed TP (2002) Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. Nucleic Acids Res 30:e15

    Article  PubMed  Google Scholar 

  • Yoon HG, Chan DW, Reynolds AB, Qin J, Wong J (2003) N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso. Mol Cell 12:723–734

    Article  CAS  PubMed  Google Scholar 

  • Yoshida R, Kimura N, Harada Y, Ohuchi N (2001) The loss of E-cadherin, alpha- and beta-catenin expression is associated with metastasis and poor prognosis in invasive breast cancer. Int J Oncol 18:513–520

    CAS  PubMed  Google Scholar 

  • Zhai B, Yan HX, Liu SQ, Chen L, Wu MC, Wang HY (2008) Reduced expression of P120 catenin in cholangiocarcinoma correlated with tumor clinicopathologic parameters. World J Gastroenterol 14:3739–3744

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Mr. Hans Helenius, Department of Biostatistics, Mr. Tero Aittokallio, Department of Information Technology, MD Riitta Aaltonen, Department of Surgery, Turku University Hospital, and Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland, for valuable help. The study was supported by Turku University Foundation, Turku University Central Hospital, and Cancer Society of South-Western Finland. The study has a research approval from the Ethical Committee of Turku University. The research was carried out in accordance with the Declaration of Helsinki. Each investigated specimen was included in the cDNA microarray study only after a written consent of patient.

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We declare that we have no conflict of interest.

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Talvinen, K., Tuikkala, J., Nykänen, M. et al. Altered expression of p120catenin predicts poor outcome in invasive breast cancer. J Cancer Res Clin Oncol 136, 1377–1387 (2010). https://doi.org/10.1007/s00432-010-0789-8

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