Nectin-4, a new serological breast cancer marker, is a substrate for tumor necrosis factor-alpha-converting enzyme (TACE)/ADAM-17.
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. Adelaide, 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-alpha 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-alpha-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.
Fabre-Lafay
Stéphanie
S
INSERM UMR 599, Cancerology Institute and Laboratoire de Pharmacologie Moléculaire, IFR 137, Cancer and Immunology Institute of Marseille, France.
Garrido-Urbani
Sarah
S
Reymond
Nicolas
N
Gonçalves
Anthony
A
Dubreuil
Patrice
P
Lopez
Marc
M
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000097:blood* / Q000378:metabolism; D001943:Breast Neoplasms / Q000097:blood* / Q000201:enzymology / Q000235:genetics; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000097:blood* / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012995:Solubility; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000075983:Nectins
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D004273:DNA, Neoplasm; D008666:Metalloendopeptidases; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C442228:NECTIN4 protein, human; D000075983:Nectins; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse