Skip to main content
SpringerLink
Log in

P-Cadherin and β-catenin are useful prognostic markers in breast cancer patients; β-catenin interacts with heat shock protein Hsp27

  • Original Paper
  • Published:
Cell Stress and Chaperones Aims and scope

Abstract

The cadherin–catenin proteins have in common with heat shock proteins (HSP) the capacity to bind/interact proteins of other classes. Moreover, there are common molecular pathways that connect the HSP response and the cadherin–catenin protein system. In the present study, we have explored whether in breast cancer the HSP might interact functionally with the cadherin–catenin cell adhesion system. β-Catenin was immunoprecipitated from breast cancer biopsy samples, and the protein complexes isolated in this way were probed with antibodies against HSP family members. We are thus the first to demonstrate a specific interaction between β-catenin and Hsp27. However, β-catenin did not bind Hsp60, Hsp70, Hsp90, gp96, or the endoplasmic reticulum stress response protein CHOP. To confirm the finding of Hsp27-β-catenin interaction, the 27-kDa immunoprecipitated band was excised from one-dimensional polyacrylamide gel electrophoresis gels and submitted to liquid chromatography–tandem mass spectrometry with electrospray ionization, confirming a role for Hsp27. In addition, β-catenin interacted with other proteins including heat shock transcription factor 1, P-cadherin, and caveolin-1. In human breast cancer biopsy samples, β-catenin was coexpressed in the same tumor areas and in the same tumor cells that expressed Hsp27. However, this coexpression was strong when β-catenin was present in the cytoplasm of the tumor cells and not when β-catenin was expressed at the cell surface only. Furthermore, murine breast cancer cells transfected with hsp25 showed a redistribution of β-catenin from the cell membrane to the cytoplasm. When the prognostic significance of cadherin–catenin expression was examined by immunohistochemistry in breast cancer patients (n = 215, follow-up = >10 years), we found that the disease-free survival and overall survival were significantly shorter for patients expressing P-cadherin and for patients showing expression of β-catenin in the cytoplasm only (not at the cell surface). The interactions of β-catenin with Hsp27 and with HSF1 may explain some of the molecular pathways that influence tumor cell survival and the clinical significance in the prognosis of the breast cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Adam L, Vadlamudi RK, McCrea P, Kumar R (2001) Tiam1 overexpression potentiates heregulin-induced lymphoid enhancer factor-1/β-catenin nuclear signaling in breast cancer cells by modulating the intercellular stability. J Biol Chem 276:28443–28450

    Article  PubMed  CAS  Google Scholar 

  • Asgeirsson KS, Jonasson JG, Tryggvadottir L, Ólafsdóttir K, Sigurgeirsdóttir JR, Ingvarsson S, Ögmundsdóttir HM (2000) Altered expression of e-cadherin in breast cancer: patterns, mechanisms and clinical significance. Eur J Cancer 361:098–1106

    Article  PubMed  CAS  Google Scholar 

  • Bausero MA, Bharti A, Page DT et al (2006) Silencing the hsp25 gene eliminates migration capability of the highly metastatic murine 4T1 breast adenocarcinoma cell. Tumor Biol 7:17–26

    Article  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 lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene 13:1919–1925

    PubMed  CAS  Google Scholar 

  • Calderwood SK, Khaleque MA, Bharti A, Ciocca DR (2007) HSF1: an emerging factor in cancer. In: Calderwood SK, Sherman MY, Ciocca DR (eds) Heat shock proteins in cancer. Springer, The Netherlands 53–71

    Chapter  Google Scholar 

  • Christians ES, Yan LJ, Benjamin IJ (2002) Heat shock factor 1 and heat shock proteins: critical partners in protection against acute cell injury. Crit Care Med 30:S43–S50

    Article  CAS  Google Scholar 

  • Ciocca DR, Calderwood S (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive and treatment implications. Cell Stress Chaperones 10:86–103

    Article  PubMed  CAS  Google Scholar 

  • Ciocca DR, Rozados VR, Cuello-Carrión FD, Gervasoni SI, Matar P, Scharovsky OG (2003) Heat shock proteins 25 and 70 in rodent tumors treated with doxorubicin and lovastatin. Cell Stress Chaperones 8:26–36

    Article  PubMed  CAS  Google Scholar 

  • Ciocca D, Gago F, Fanelli M, Calderwood S (2006) Co-expression of steroid receptors (estrogen receptor alpha and/or progesterone receptors) and Her-2/new: clinical implications. J Steroid Biochem Mol Biol 102:32–40

    Article  PubMed  CAS  Google Scholar 

  • Cobanoglu U, Ersoz S, Turgutalp H, Reis A, Ozoran Y (2004) Correlation of E-cadherin expression with clinicopathological parameters in breast carcinoma. Saudi Med J 25:1024–1027

    PubMed  Google Scholar 

  • Cross DA, Alessi DE, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789

    Article  PubMed  CAS  Google Scholar 

  • Dann CE, Hsieh JC, Rattner A, Sharma D, Nathans J, Leahy DJ (2001) Insights into WNT binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature (Lond) 412:86–90

    Article  CAS  Google Scholar 

  • Dolled-Filhart M, McCabe A, Giltnane J, Cregger M, Camp RL, Rimm DL (2006) Quantitative in situ analysis of beta-catenin expression in breast cancer shows decreased expression is associated with poor outcome. Cancer Res 66:5487–5494

    Article  PubMed  CAS  Google Scholar 

  • Droufakou S, Deshmane V, Roylance R, Hanby A, Tomlinson I, Hart I (2001) Multiple ways of silencing E-cadherin gene expression in lobular carcinoma of the breast. Int J Cancer 92:404–408

    Article  PubMed  CAS  Google Scholar 

  • Fanelli MA, Cuello-Carrión FD, Dekker J, Schoemaker J, Ciocca DR (1998) Serological detection of heat shock protein hsp27 in normal and breast cancer patients. Cancer Epidemiol Biomarkers Prev 7:791–795

    PubMed  CAS  Google Scholar 

  • Foty RA, Steinberg MS (2005) The differential adhesion hypothesis: a direct evaluation. Dev Biol 278:255–263

    Article  PubMed  CAS  Google Scholar 

  • Gago FE, Tello OM, Diblasi AM, Ciocca DR (1998) Integration of estrogen and progesterone receptors with pathological and molecular prognostic factors in breast cancer patients. J Steroid Biochem Mol Biol 67:431–437

    Article  PubMed  CAS  Google Scholar 

  • Galbiati F, Volonte D, Brown AM, Weinstein DE, Ben-Zeèv A, Pestell RG, Lisanti MP (2000) Caveolin-1 expression inhibits Wnt/ β-catenin/Lef-1 signaling by recruiting β-catenin to caveolae membrane domains. J Biol Chem 275:23368–23377

    Article  PubMed  CAS  Google Scholar 

  • Gamallo C, Moreno-Bueno G, Sarrio D, Calero F, Hardisson D, Palacios J (2001) The prognostic significance of P-cadherin in infiltrating ductal breast carcinoma. Mod Pathol 14:650–654

    Article  PubMed  CAS  Google Scholar 

  • Gillet CE, Miles DW, Ryder K, Skilton D, Liebman RD, Springall RJ, Barnes DM, Hanby AM (2001) Retention of the expression of e-cadherin and catenins is associated with shorter survival in grade III ductal carcinoma of the breast. J Pathol 93:433–441

    Article  Google Scholar 

  • Gonzalez MA, Pinder SE, Wencyk PM et al (1999) An immunohistochemical examination of the expression of E-cadherin, and α and β/γ- catenin and α2- and β1 integrins in invasive breast cancer. J Pathol 187:523–529

    Article  PubMed  CAS  Google Scholar 

  • Gumbiner BM (2000) Regulation of cadherin adhesive activity. J Cell Biol 148:399–404

    Article  PubMed  CAS  Google Scholar 

  • Heimann R, Lan F, McBride R, Hellman S (2000) Separating favorable from unfavorable prognostic markers in breast cancer: the role of E-cadherin. Cancer Res 60:298–304

    PubMed  CAS  Google Scholar 

  • Howard EM, Lau SK, Lyles RH, Birdsong GG, Umbreit JN, Kochhar R (2005) Expression of e-cadherin in high-risk breast cancer. J Cancer Res Clin Oncol 131:14–18

    Article  PubMed  CAS  Google Scholar 

  • Jacquemier J, Ginester C, Rougemont J et al (2005) Protein expression profiling identifies subclasses of breast cancer and predicts prognosis. Cancer Res 65:767–769

    PubMed  CAS  Google Scholar 

  • Kovács A, Walker R, Nagy A, Gomba S, Jones L, Dearing S (2002) Immunohistochemical study of P-cadherin in breast cancer. Orv Hetil 143:405–409

    PubMed  Google Scholar 

  • Kovács A, Dhillon J, Walker R (2003) Expression of P-cadherin, but not E-cadherin or N-cadherin, relates to pathological and functional differentiation of breast carcinomas. Mol Pathol 56:318–322

    Article  PubMed  Google Scholar 

  • Karayiannakis A, Nakopoulou L, Gakiopoulou H, Keramopoulous A, Davaris P, Pignatelli M (2001) Expression patterns of β-catenin in in situ and invasive breast cancer. EJSO 27:31–36

    Article  PubMed  CAS  Google Scholar 

  • Kariola R, Abdel-Rahman W, Ollikainen M, Butzow R, Peltomaki P, Nystrom M (2005) APC and beta-catenin protein expression patterns in HNPCC-related endometrial and colorectal cancers. Fam Cancer 4:187–190

    Article  PubMed  CAS  Google Scholar 

  • Khaleque A, Bharti A, Sawyer D, Gong J, BenjaminI B, Stevenson MA, Calderwood SK (2005) Induction of heat shock proteins by heregulin β1 leads to protection from apoptosis and anchorage-independent growth. Oncogene 00:1–10

    Google Scholar 

  • Kouzmenko A, Takeyama K, Ito S et al (2004) Wnt/β-catenin and estrogen signaling converge in vivo. J Biol Chem 279:40255–40258

    Article  PubMed  CAS  Google Scholar 

  • Larne L, Delmas Y (2006) The Wnt/Beta-catenin pathway in melanoma. Front Biosci 11:733–742

    Article  Google Scholar 

  • Li Y, Wei ZM, Meng YX, Ji XR (2005) β-Catenin up-regulates the expression of cyclin D1, c-myc and MMP-7 in human pancreatic cancer: relationships with carcinogenesis and metastasis. World J Gastroenterol 11:2117–2123

    PubMed  CAS  Google Scholar 

  • Lim SCH, Lee MS (2002) Significance of E-cadherin/β-catenin complex and cyclin D1 in breast cancer. Oncol Rep 9:915–928

    PubMed  CAS  Google Scholar 

  • Lin S, Xia W, Wang J, Kwong KY, Spohn B, Wen Y, Pestell RG, Hung MC (1999) β-Catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci USA 97:4262–4266

    Article  Google Scholar 

  • Mackay A, Jones CH, Dexter T, Silva RL, Bulmer K, Jones A, Simpson P, Harris RA, Jat PS, Neville AM, Reis LF, Lakhani SR, O’Hare MJ (2003) cDNA microarray analysis of genes associated with ERBB2 (HER2/neu) overexpression in human mammary luminal epithelial cells. Oncogene 22:2680–2688

    Article  PubMed  CAS  Google Scholar 

  • Monick MM, Carter AB, Robeff PK, Flaherty DM, Peterson MW, Hunninghake GW (2001) Lipopolysaccharide activates Akt in human alveolar macrophages resulting in nuclear accumulation and transcriptional activity of β-catenin. J Immunol 166:4713–4720

    PubMed  CAS  Google Scholar 

  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Volgestein B, Kinzler KW (1997) Activation of β-catenin–Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 275:1787–1790

    Article  PubMed  CAS  Google Scholar 

  • Nakopoulou L, Gakiopoulou-Givalou H, Karayiannakis A, Giannopoulou I, Keramopoulos A, Davaris P, Pignatelli M (2002) Abnormal α-catenin expression in invasive breast cancer correlates with poor patient survival. Histopathology 40:536–46

    Article  PubMed  CAS  Google Scholar 

  • Palacios J, Benito N, Pizarro A, Suarez A, Espada J, Cano A, Gamallo C (1995) Anomalous expression of P-cadherin in breast carcinoma. Correlation with E-cadherin expression and pathological features. Am J Pathol 147:605–612

    Google Scholar 

  • Paredes J, Milanezi F, Reis-Filho JS, Leitao D, Athanazio D, Schmitt F (2002) Aberrant P-cadherin expression: is it associated with estrogen-independet growth in breat cancer? Pathol Res Pract 198:795–801

    Article  PubMed  CAS  Google Scholar 

  • Paredes J, Stove CV, Milanezi F, Van Marck V, Derycke lL, Mareel M, Bracke M, Schmitt F (2004) P-cadherin is up-regulated by antiestrogen ICI 182,780 and promotes invasion of human breast cancer cells. Cancer Res 64:8309–8317

    Article  PubMed  CAS  Google Scholar 

  • Paredes J, Albergaria A, Oliveira JT, Jerónimo C, Milanezi F, Schmitt FC (2005) P-Cadherin overexpression is an indicator of clinical outcome in invasive breast carcinomas and is associated with CDH3 promoter hypomethylation. Clin Cancer Res 11:5869–5877

    Article  PubMed  CAS  Google Scholar 

  • Patel IS, Madan P, Getios S, Bertrand MA, MacCalman CD (2003) Cadhering switching in ovarian cancer progression. Int J Cancer 106:172–177

    Article  PubMed  CAS  Google Scholar 

  • Pawlowski JE, Ertel JR, Allen MP, Xu M, Butler C, Wilson EM, Wierman ME (2002) Liganded androgen receptor interaction with beta-catenin: nuclear co-localization and modulation of transcriptional activity in neuronal cells. J Biol Chem 277:20702–20710

    Article  PubMed  CAS  Google Scholar 

  • Peralta Soler A, Knudsen K, Salazar H, Han A, Keshgegian A (1999) P-cadherin expression in breast carcinoma indicates poor survival. Cancer 86:1263–1272

    Article  PubMed  CAS  Google Scholar 

  • Rasbridge SA, Gillett CE, Sampson SA, Walsh FS, Mills RR (1993) Epithelial (E-) and placental (P-) cadherin cell adhesion molecules expression in breast carcinoma. J Pathol 169:245–250

    Article  PubMed  CAS  Google Scholar 

  • Rhan JJ, Dabbagh L, Pasdar M, Hugh JC (2001) The importance of MUC1 cellular localization in patients with breast carcinoma: an immunohistologic study of 71 patients and review of the literature. Cancer 91:1973–1982

    Article  Google Scholar 

  • Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P (1993) Association of the APC gene product with β-catenin. Science 262:1731–1734

    Article  PubMed  CAS  Google Scholar 

  • Ryo A, Nakamura M, Wulf G, Liou Y, Lu KP (2001) Pin1 regulates turnover and subcellular localization of β-catenin by inhibiting its interaction with APC. Nat Cell Biol 3:793–801

    Article  PubMed  CAS  Google Scholar 

  • Shimura T, Takenaka Y, Tsutsumi S, Hogan V, Kikuchi A, Raz A (2004) Galectin-3, a novel binding partner of β-catenin. Cancer Res 64:6363–6367

    Article  PubMed  CAS  Google Scholar 

  • Siitonen SM, Kononen JT, Helin HJ, Rantala IS, Holli KA, Isola JJ (1996) Reduced E-cadherin expression is associated with invasiveness and unfavorable prognosis in breast cancer. Am J Clin Pathol 105:394–402

    PubMed  CAS  Google Scholar 

  • Taniuchi K, Nakagawa H, Hosokawa M, Nakamura T, Eguchi H, Ohigashi H, Ishikawa O, Katagiri T, Nakamura Y (2005) Overexpressed P-cadherin/CDH3 promotes motility of pancreatic cells by interacting with p120ctn and activating rho-family GTPases. Cancer Res 65:3092–3099

    PubMed  CAS  Google Scholar 

  • Van’t Veer LJ, Dai H, Van de Vijver MJ (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–546

    Article  CAS  Google Scholar 

  • Vargas-Roig LM, Gago FE, Tello O, Aznar JC, Ciocca DR (1998) Heat shock protein expression and drug resistance in breast cancer patients treated with induction chemotherapy. Int J Cancer (Pred Oncol) 79:468–475

    Article  CAS  Google Scholar 

  • Wheelock MJ, Peralta Soler A, Knudsen KA (2001) Cadherin junctions in mammary tumors. J Mammary Gland Biol Neoplasia 6:275–285

    Article  PubMed  CAS  Google Scholar 

  • Yamada S, Pokutta S, Drees F, Weis WI, Nelson WJ (2005) Deconstructing the cadherin–catenin–actin complex. Cell 123:889–901

    Article  PubMed  CAS  Google Scholar 

  • Yang F, Li X, Sharma M, Sasaki CY, Longo DL, Lim B, Sun Z (2002) Linking beta-catenin to androgen-signaling pathway. J Biol Chem 277:11336–11344

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors appreciate the excellent technical support provided by Arturo O. Stati, Esteban Azar, and Remedios Marin. We are very grateful to Dr. Stuart Calderwood for his helpful assistance in the editing process.

Author information

Authors and Affiliations

  1. Oncology Laboratory, Institute of Experimental Medicine and Biology of Cuyo, Regional Center for Scientific and Technological Research, National Research Council (CONICET), Mendoza, Argentina

    Mariel A. Fanelli, Magdalena Montt-Guevara, Angela M. Diblasi, F. Darío Cuello-Carrión & Daniel R. Ciocca

  2. Department of Gynaecology, Medical School, National University of Cuyo, Mendoza, Argentina

    Francisco E. Gago

  3. Private Pathology Laboratory, Mendoza, 5500, Argentina

    Olga Tello

  4. Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, Vermillion, SD, 57069, USA

    Eduardo Callegari

  5. Programa Cancer Institut Pasteur du Montevideo, 11400, Montevideo, Uruguay

    Maria A. Bausero

  6. Oncology Laboratory, Institute of Experimental Medicine and Biology of Cuyo, IMBECU-CRICYT, Casilla de Correo 855, Mendoza, 5500, Argentina

    Mariel A. Fanelli

Authors
  1. Mariel A. Fanelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Magdalena Montt-Guevara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angela M. Diblasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francisco E. Gago
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Olga Tello
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F. Darío Cuello-Carrión
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eduardo Callegari
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Maria A. Bausero
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daniel R. Ciocca
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mariel A. Fanelli.

Additional information

This study was supported by the National Research Council of Argentina (PIP 5149-CONICET) and the Argentine Foundation for Cancer Research.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fanelli, M.A., Montt-Guevara, M., Diblasi, A.M. et al. P-Cadherin and β-catenin are useful prognostic markers in breast cancer patients; β-catenin interacts with heat shock protein Hsp27. Cell Stress and Chaperones 13, 207–220 (2008). https://doi.org/10.1007/s12192-007-0007-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12192-007-0007-z

Keywords

Search

Navigation