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J. Biol. Chem., Vol. 280, Issue 20, 19543-19550, May 20, 2005

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Nectin-4, a New Serological Breast Cancer Marker, Is a Substrate for Tumor Necrosis Factor--converting Enzyme (TACE)/ADAM-17^*

Stéphanie Fabre-Lafay, Sarah Garrido-Urbani, Nicolas Reymond, Anthony Gonçalves¶, Patrice Dubreuil, and Marc Lopez||

From the INSERM UMR 599, Cancerology Institute and ^¶Laboratoire de Pharmacologie Moléculaire, IFR 137, Cancer and Immunology Institute of Marseille, 27 Bvd. Leï-roure, 13009 Marseille, France

Serum markers are extensively used in diagnostic and follow-up of cancer patients. We recently described Nectin-4, a 66-kDa adhesion molecule of the Nectin family, which is a valuable new histological and serological marker for breast carcinoma. In vivo, Nectin-4 is re-expressed in breast carcinoma, and a circulating form of Nectin-4 is detected in the sera of patients with metastatic breast cancer. In vitro, a soluble form of Nectin-4 is produced in the supernatant of breast tumor cell lines (S. Fabre-Lafay, C. Ginestier, S. Garrido-Urbani, C. Berruyer, R. Sauvan, N. Reymond, J. Adélaide, J. Geneix, P. Dubreuil, J. Jacquemier, D. Birnbaum, and M. Lopez, manuscript in preparation). We have investigated the mechanisms that regulate the production of this soluble form. It was found that the soluble form of Nectin-4 detected in the sera of patients and the supernatant of breast tumor cell lines share similar biochemical and immunological features. The soluble Nectin-4 form (43 kDa) is formed by the entire Nectin-4 ectodomain. Nectin-4 shedding is constitutive, strongly enhanced by 12-O-tetradecanoylphorbol-13-acetate activation, and reduced tumor necrosis factor- protease inhibitor TAPI-1 or by the tissue inhibitor of metalloproteinase-3 (TIMP-3). TAPI-1 and TIMP-3 are inhibitors of the endoprotease tumor necrosis factor--converting enzyme (TACE)/ADAM-17. Overexpression or small interfering RNA-mediated silencing of TACE enhanced or reduced Nectin-4 shedding, respectively. Nectin-4 is not shed when expressed in TACE-deficient fibroblasts. Interestingly, the active form of TACE is overexpressed in breast tumors and may indicate that TACE is responsible for Nectin-4 shedding not only in vitro but also in vivo.

Received for publication, September 23, 2004 , and in revised form, March 21, 2005.

^* This study was funded by INSERM, the Ligue Nationale Française Contre le Cancer, and the Association pour la Recherche sur le Cancer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed to this work.

^|| To whom correspondence should be addressed. Tel.: 33-4-91-75-84-17; Fax: 33-4-91-26-3-64; E-mail: lopez{at}marseille.inserm.fr.

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