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Molecular and Cellular Biology, February 2008, p. 1114-1123, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01335-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Role of WISP-2/CCN5 in the Maintenance of a Differentiated and Noninvasive Phenotype in Human Breast Cancer Cells{triangledown}

Asmaà Fritah,1,{dagger},{ddagger} Cécile Saucier,1,{dagger} Olivier De Wever,2 Marc Bracke,2 Ivan Bièche,3 Rosette Lidereau,3 Christian Gespach,1 Sylvain Drouot,1 Gérard Redeuilh,1 and Michèle Sabbah1*

INSERM, U673, Hôpital Saint-Antoine, Université Pierre et Marie Curie (UPMC-Paris 6), Paris, France,1 Laboratory of Experimental Cancerology, Department of Radiotherapy and Nuclear Medicine, Ghent University Hospital, Ghent University, Ghent, Belgium,2 INSERM, U735, Saint-Cloud, France, and Centre René Huguenin, FNCLCC, Saint-Cloud, France3

Received 25 July 2007/ Returned for modification 29 August 2007/ Accepted 16 November 2007

WISP-2/CCN5 is an estrogen-regulated member of the "connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed" (CCN) family of the cell growth and differentiation regulators. The WISP-2/CCN5 mRNA transcript is undetectable in normal human mammary cells, as well as in highly aggressive breast cancer cell lines, in contrast with its higher level in the breast cancer cell lines characterized by a more differentiated phenotype. We report here that knockdown of WISP-2/CCN5 by RNA interference in estrogen receptor alpha (ER{alpha})-positive MCF-7 breast cancer cells induced an estradiol-independent growth linked to a loss of ER{alpha} expression and promoted epithelial-to-mesenchymal transdifferentiation. In contrast, forced expression of WISP-2/CCN5 directed MCF-7 cells toward a more differentiated phenotype. When introduced into the poorly differentiated, estrogen-independent, and invasive MDA-MB-231 breast cancer cells, WISP-2/CCN5 was able to reduce their proliferative and invasive phenotypes. In a series of ER{alpha}-positive tumor biopsies, we found a positive correlation between the expression of WISP-2/CCN5 and ID2, a transcriptional regulator of differentiation in normal and transformed breast cells. We propose that WISP-2/CCN5 is an important regulator involved in the maintenance of a differentiated phenotype in breast tumor epithelial cells and may play a role in tumor cell invasion and metastasis.

* Corresponding author. Mailing address: INSERM 673, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571 Paris cedex 12, France. Phone: 0033 149 28 46 14. Fax: 0033 144 74 93 18. E-mail: sabbah{at}st-antoine.inserm.fr

{triangledown} Published ahead of print on 18 December 2007.

{dagger} These authors contributed equally to the study.

{ddagger} Present address: Institute of Reproductive and Developmental Biology, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom.

Molecular and Cellular Biology, February 2008, p. 1114-1123, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01335-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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