Journal Mobile Options
Table of Contents
Vol. 185, No. 1-3, 2007
Issue release date: June 2007
Section title: Paper
Cells Tissues Organs 2007;185:95–99
(DOI:10.1159/000101308)

CCN6 (WISP3) as a New Regulator of the Epithelial Phenotype in Breast Cancer

Kleer C.G. · Zhang Y. · Merajver S.D.
Departments of aPathology and bInternal Medicine, Division of Hematology/Oncology, and cComprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Mich., USA

Do you have an account?

Register and profit from personalized services (MyKarger) Login Information

Please create your User ID & Password





Contact Information









I have read the Karger Terms and Conditions and agree.

Register and profit from personalized services (MyKarger) Login Information

Please create your User ID & Password





Contact Information









I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Buy

  • FullText & PDF
  • Unlimited re-access via MyKarger (new!)
  • Unrestricted printing, no saving restrictions for personal use
  • Reduced rates with a PPV account
read more

Direct: USD 38.00
Account: USD 26.50

Select

Rent/Cloud

  • Rent for 48h to view
  • Buy Cloud Access for unlimited viewing via different devices
  • Synchronizing in the ReadCube Cloud
  • Printing and saving restriction apply

Rental: USD 8.50
Cloud: USD 20.00

Select

Subscribe

  • Automatic perpetual access to all articles of the subscribed year(s)
  • Unlimited re-access via Subscriber Login or MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more

Subcription rates


Select


Article / Publication Details

First-Page Preview
Abstract of Paper

Received: 3/27/2006
Accepted: 10/3/2006
Published online: 6/25/2007

Number of Print Pages: 5
Number of Figures: 2
Number of Tables: 0

ISSN: 1422-6405 (Print)
eISSN: 1422-6421 (Online)

For additional information: http://www.karger.com/CTO

Abstract

CCN6 (WISP3) is a cysteine-rich secreted protein that belongs to the CCN (Cyr61, CTGF, Nov) family of genes. We found that CCN6 mRNA is reduced in 80% of cases of the most lethal form of locally advanced breast cancer, inflammatory breast cancer. CCN6 contains four highly conserved motifs with sequence similarities to insulin-like growth factor binding proteins, von Willebrand type C, thrombospondin 1, and a carboxyl-terminal domain putatively involved in dimerization. CCN6 has tumor growth-, proliferation-, and invasion-inhibitory functions in breast cancer. Recently, by using a small infering RNA to downregulate CCN6 in immortalized human mammary epithelial cells, CCN6 was found to be essential to induce the process of epithelial-mesenchymal transition (EMT) with repression of E-cadherin gene expression and induction of a protein expression program characteristic of EMT. This review will focus on the current knowledge regarding the function of CCN6 in breast cancer with special emphasis on the emerging role of CCN6 as a regulator of the epithelial phenotype and E-cadherin expression in the breast.


Article / Publication Details

First-Page Preview
Abstract of Paper

Received: 3/27/2006
Accepted: 10/3/2006
Published online: 6/25/2007

Number of Print Pages: 5
Number of Figures: 2
Number of Tables: 0

ISSN: 1422-6405 (Print)
eISSN: 1422-6421 (Online)

For additional information: http://www.karger.com/CTO


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Allen, N.E., A.W. Roddam, D.S. Allen, I.S. Fentiman, I. Dos Santos Silva, J. Peto, J.M. Holly, T.J. Key (2005) A prospective study of serum insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding protein-3 and breast cancer risk. Br J Cancer 92: 1283–1287.
  2. Benini, S., B. Perbal, D. Zambelli, M.P. Colombo, M.C. Manara, M. Serra, M. Parenza, V. Martinez, P. Picci, K. Scotlandi (2005) In Ewing’s sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type. Oncogene 24: 4349–4361.
  3. Bleau, A.M., N. Planque, B. Perbal (2005) CCN proteins and cancer: two to tango. Front Biosci 10: 998–1009.
  4. Brigstock, D.R., R. Goldschmeding, K.I. Katsube, S.C. Lam, L.F. Lau, K. Lyons, C. Naus, B. Perbal, B. Riser, M. Takigawa, H. Yeger (2003) Proposal for a unified CCN nomenclature. Mol Pathol 56: 127–128.
  5. Brigstock, D., L. Lau, B. Perbal (2005) CCN workshop. J Clin Pathol 58: 463–465.
  6. Byrne, C., G.A. Colditz, W.C. Willett, F.E. Speizer, M. Pollak, S.E. Hankinson (2000) Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and mammographic density. Cancer Res 60: 3744–3748.
  7. Byun, D., S. Mohan, D.J. Baylink, X. Qin (2001) Localization of the IGF binding domain and evaluation of the role of cysteine residues in IGF binding in IGF binding protein-4. J Endocrinol 169: 135–143.
  8. Davis, L., Y. Chen, M. Sen (2006) WISP-3 functions as a ligand and promotes superoxide dismutase activity. Biochem Biophys Res Commun 342: 259–265.
  9. Diorio, C., M. Pollak, C. Byrne, B. Masse, N. Hebert-Croteau, M. Yaffe, G. Cote, S. Berube, C. Morin, J. Brisson (2005) Insulin-like growth factor-I, IGF-binding protein-3, and mammographic breast density. Cancer Epidemiol Biomarkers Prev 14: 1065–1073.
  10. Grotendorst, G.R., M.R. Duncan (2005) Individual domains of connective tissue growth factor regulate fibroblast proliferation and myofibroblast differentiation. FASEB J 19: 729–738.
  11. Hurvitz, J.R., W.M. Suwairi, W. Van Hul, H. El-Shanti, A. Superti-Furga, J. Roudier, D. Holderbaum, R.M. Pauli, J.K. Herd, E.V. Van Hul, H. Rezai-Delui, E. Legius, M. Le Merrer, J. Al-Alami, S.A. Bahabri, M.L. Warman (1999) Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet 23: 94–98.
  12. Imai, Y., A. Moralez, U. Andag, J.B. Clarke, W.H. Busby Jr, D.R. Clemmons (2000) Substitutions for hydrophobic amino acids in the N-terminal domains of IGFBP-3 and -5 markedly reduce IGF-I binding and alter their biologic actions. J Biol Chem 275: 18188–18194.
  13. Jaiyesimi, I.A., A.U. Buzdar, G. Hortobagyi (1992) Inflammatory breast cancer: a review. J Clin Oncol 10: 1014–1024.
  14. Kleer, C.G., K.L. van Golen, T. Braun, S.D. Merajver (2001) Persistent E-cadherin expression in inflammatory breast cancer. Mod Pathol 14: 458–464.
  15. Kleer, C.G., Y. Zhang, Q. Pan, K.L. van Golen, Z.F. Wu, D. Livant, S.D. Merajver (2002) WISP3 is a novel tumor suppressor gene of inflammatory breast cancer. Oncogene 21: 3172–3180.
  16. Kleer, C.G., Y. Zhang, Q. Pan, S.D. Merajver (2004) WISP3 (CCN6) is a secreted tumor-suppressor protein that modulates IGF signaling in inflammatory breast cancer. Neoplasia 6: 179–185.
  17. Kowalski, P.J., M.A. Rubin, C.G. Kleer (2003) E-cadherin expression in primary carcinomas of the breast and its distant metastases. Breast Cancer Res 5: R217–R222.
  18. Lau, L.F., S.C. Lam (1999) The CCN family of angiogenic regulators: the integrin connection. Exp Cell Res 248: 44–57.
  19. Lee, B.J., N.D. Tannenbaum (1924) Inflammatory carcinoma of the breast: a report of twenty-eight cases from the breast clinic of Memorial Hospital. Surg Gynecol Obstet 39: 580–595.
  20. Li, C.L., V. Martinez, B. He, A. Lombet, B. Perbal (2002) A role for CCN3 (NOV) in calcium signalling. Mol Pathol 55: 250–261.
  21. Lin, C.G., S.J. Leu, N. Chen, C.M. Tebeau, S.X. Lin, C.Y. Yeung, L.F. Lau (2003) CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family. J Biol Chem 278: 24200–24208.
  22. Lin, C.G., C.C. Chen, S.J. Leu, T.M. Grzeszkiewicz, L.F. Lau (2005) Integrin-dependent functions of the angiogenic inducer NOV (CCN3): implication in wound healing. J Biol Chem 280: 8229–8237.
  23. Manara, M.C., B. Perbal, S. Benini, R. Strammiello, V. Cerisano, S. Perdichizzi, M. Serra, A. Astolfi, F. Bertoni, J. Alami, H. Yeger, P. Picci, K. Scotlandi (2002) The expression of ccn3(nov) gene in musculoskeletal tumors. Am J Pathol 160: 849–859.
  24. Oka, H., H. Shiozaki, K. Kobayashi, M. Inoue, H. Tahara, T. Kobayashi, Y. Takatsuka, N. Matsuyoshi, S. Hirano, M. Takeichi, et al. (1993) Expression of E-cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis. Cancer Res 53: 1696–1701.
  25. Palacios, J., N. Benito, A. Pizarro, A. Suarez, J. Espada, A. Cano, C. Gamallo (1995) Anomalous expression of P-cadherin in breast carcinoma. Correlation with E-cadherin expression and pathological features. Am J Pathol 146: 605–612.
  26. Pennica, D., T.A. Swanson, J.W. Welsh, M.A. Roy, D.A. Lawrence, J. Lee, J. Brush, L.A. Taneyhill, B. Deuel, M. Lew, C. Watanabe, R.L. Cohen, M.F. Melhem, G.G. Finley, P. Quirke, A.D. Goddard, K.J. Hillan, A.L. Gurney, D. Botstein, A.J. Levine (1998) WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc Natl Acad Sci USA 95: 14717–14722.
  27. Perbal, B. (2001) NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues. Mol Pathol 54: 57–79.
  28. Perbal, B., C. Martinerie, R. Sainson, M. Werner, B. He, B. Roizman (1999a) The C-terminal domain of the regulatory protein NOVH is sufficient to promote interaction with fibulin 1C: a clue for a role of NOVH in cell-adhesion signaling. Proc Natl Acad Sci USA 96: 869–874.
  29. Perbal, B., C. Martinerie, R. Sainson, M. Werner, B. He, B. Roizman (1999b) The C-terminal domain of the regulatory protein NOVH is sufficient to promote interaction with fibulin 1C: a clue for a role of NOVH in cell-adhesion signaling. Proc Natl Acad Sci USA 96: 869–874.
  30. Rasbridge, S.A., C.E. Gillett, S.A. Sampson, F.S. Walsh, R.R. Millis (1993) Epithelial (E-) and placental (P-) cadherin cell adhesion molecule expression in breast carcinoma. J Pathol 169: 245–250.
  31. Sakamoto, K., S. Yamaguchi, R. Ando, A. Miyawaki, Y. Kabasawa, M. Takagi, C.L. Li, B. Perbal, K. Katsube (2002) The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway. J Biol Chem 277: 29399–29405.
  32. Schernhammer, E.S., J.M. Holly, M.N. Pollak, S.E. Hankinson (2005) Circulating levels of insulin-like growth factors, their binding proteins, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 14: 699–704.
  33. van Golen, K.L., S. Davies, Z.F. Wu, Y. Wang, C.D. Bucana, H. Root, S. Chandrasekharappa, M. Strawderman, S.P. Ethier, S.D. Merajver (1999) A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clin Cancer Res 5: 2511–2519.
  34. Yang, G.P., L.F. Lau (1991) Cyr61, product of a growth factor-inducible immediate early gene, is associated with the extracellular matrix and the cell surface. Cell Growth Differ 2: 351–357.
  35. Zhang, Y., Q. Pan, H. Zhong, S.D. Merajver, C.G. Kleer (2005) Inhibition of CCN6 (WISP3) expression promotes neoplastic progression and enhances the effects of insulin-like growth factor-1 on breast epithelial cells. Breast Cancer Res 7: R1080–R1089.