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ADAM28 Is Overexpressed in Human Breast

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ADAM28 Is Overexpressed in Human Breast Research Article ADAM28 Is Overexpressed in Human Breast Carcinomas: Implications for Carcinoma Cell Proliferation through Cleavage of Insulin-like Growth Factor Binding Protein-3 Yoko Mitsui,1,2 Satsuki Mochizuki,1 Takahide Kodama,1 Masayuki Shimoda,1 Takashi Ohtsuka,1 Takayuki Shiomi,1 Miyuki Chijiiwa,1 Tadashi Ikeda,2 Masaki Kitajima,2 and Yasunori Okada1 Departments of 1Pathology and 2Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan Abstract domain structure composed of a signal sequence and the following domains: propeptide, metalloproteinase, disintegrin, cysteine-rich, A disintegrin and metalloproteinases (ADAMs) are involved in epidermal growth factor-like, transmembrane, and cytoplasmic various biological events including cell adhesion, cell fusion, domains (2–5). Thirty-three members have been identified in membrane protein shedding, and proteolysis. In the present mammalian species, Caenorhabditis elegans, Xenopus, and Dro- study, our reverse transcription-PCRanalysis showed that sophila.3 However, only one third of the members possess the zinc- among the 12 different ADAM species with a putative binding consensus motif in their metalloproteinase domains (4, 5). metalloproteinase motif, prototype membrane-anchored These metalloproteinase-type ADAM proteins play a role in ADAM28m and secreted-type ADAM28s are selectively shedding of membrane proteins, cell adhesion, cell fusion, and expressed in human breast carcinoma tissues. By real-time cell signaling (2, 3, 6–9). ADAM28 is one of the metalloproteinase- quantitative PCR, their expression levels were significantly type ADAMs and is expressed in two alternative forms [i.e., a higher in carcinomas than in nonneoplastic breast tissues. prototype membrane-anchored form (ADAM28m) and a short In situ hybridization, immunohistochemistry, and immuno- secreted form (ADAM28s); ref. 10]. ADAM28 cleaves myelin basic blotting analyses indicated that ADAM28 is predominantly protein and the ectodomain of CD23 (11, 12). In addition, we have expressed in an active form by carcinoma cells within recently reported that ADAM28, prepared by activation of the carcinoma tissues. A direct correlation was observed between precursor with matrix metalloproteinase (MMP)-7, releases insulin- mRNA expression levels and proliferative activity of the like growth factor (IGF)-I from the IGF-I/IGF binding protein carcinoma cells. Treatment of ADAM28-expressing breast (IGFBP)-3 complex by selective digestion of IGFBP-3 into the two carcinoma cells (MDA-MB231) with insulin-like growth major fragments (13). factor-I (IGF-I) increased cell proliferation, cleavage of IGF A characteristic of malignant tumor cells is their ability to binding protein (IGFBP)-3, as well as IGF-I cell signaling; these autonomously proliferate, invade surrounding tissues, and metas- processes were all significantly inhibited by treatment with tasize to distant organs. Accumulated lines of evidence have shown ADAM inhibitor or anti-ADAM28 antibody. Down-regulation that MMPs play an important role in tumorigenesis and of ADAM28 expression in MDA-MB231 cells with small progression of various human cancers including breast carcinomas interfering RNA significantly reduced cell proliferation, through degradation of the extracellular matrix such as basement IGFBP-3 cleavage, and growth of xenografts in mice. In membrane components (14, 15). Because the catalytic site within addition, cleavage of IGFBP-3 in breast carcinoma tissues the metalloproteinase domain of ADAMs has high sequence was correlated with ADAM28 expression levels and inhibited homology to that of MMPs, it is expected that similar to MMPs, by treatment with ADAM inhibitor or anti-ADAM28 antibody. ADAMs may be involved in carcinogenesis as well as in invasion These results show that ADAM28 is overexpressed in an and metastases of human breast carcinomas, as they are expressed activated form in human breast carcinoma cells and suggest and activated within carcinoma tissues. The expression of ADAM9 that ADAM28 is involved in cell proliferation through (16) and ADAM12 (17) has been shown in human breast enhanced bioavailability of IGF-I released from the IGF-I/ carcinomas, and ADAM10, 15, 17, and 20 are expressed in gastric IGFBP-3 complex by selective IGFBP-3 cleavage in human carcinomas (18). Our previous study also showed that ADAM12 is breast carcinomas. (Cancer Res 2006; 66(20): 9913-20) overexpressed in an active form by glioblastoma cells in human astrocytic tumors and is involved in glioma cell proliferation (19). Introduction In addition, we have recently reported that ADAM28s and A disintegrin and metalloproteinases (ADAMs) are a recently ADAM28m are overexpressed by carcinoma cells in human non– discovered gene family of proteins with sequence similarity to the small-cell lung carcinomas (20). However, there have been no reprolysin family of snake venomases (1). Typical members of the systematic studies on the expression of ADAM family members in ADAM family are type I transmembrane proteins with a unique human breast carcinomas and little is known about the role of ADAM28 in these carcinomas. In the present study, we screened the expression of 12 different Note: Y. Mitsui and S. Mochizuki contributed equally to this work. metalloproteinase-type ADAM species and found selective expres- Requests for reprints: Yasunori Okada, Department of Pathology, School of sion of ADAM28 in human invasive breast carcinoma tissues. Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku Tokyo 160-0016, Japan. Phone: 81-3-5363-3763; Fax: 81-3-3353-3290; E-mail: [email protected]. I2006 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-06-0377 3 See http://www.people.virginia.edu/%7Ejw7g/Table_of_the_ADAMs.html. www.aacrjournals.org 9913 Cancer Res 2006; 66: (20). October 15, 2006 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2006 American Association for Cancer Research. Cancer Research ADAM28 expression was compared with clinicopathologic variables Canada), or anti-h-actin antibody (0.2 Ag/mL; Sigma-Aldrich, St. Louis, MO); and its tissue localization in carcinomas was determined by immunoreactive protein bands were detected with enhanced chemilumi- in situ hybridization and immunohistochemistry. We also examined nescence Western blotting reagents (Amersham Pharmacia Biotech, the implications of ADAM28 in breast carcinoma cell proliferation, Piscataway, NJ; ref. 20). To study the effects of a synthetic ADAM inhibitor (KB-R7785; a kind gift from Dr. Koichiro Yoshino, Carnabioscience, Kobe, IGFBP-3 degradation, and IGF-I-induced cell signaling. The results Japan; refs. 8, 13) or anti-ADAM28 antibody (297-2F3; ref. 20) on IGFBP-3 provide the first evidence that ADAM28 is overexpressed in breast cleavage in breast carcinomas, carcinoma tissue fragments (f3 Â 3 Â 2 carcinoma cells and promotes carcinoma cell proliferation through mm) were cultured in serum-free DMEM for 24 to 48 hours in the presence degradation of IGFBP-3. or absence of 1 Amol/L KB-R7785 or 5 Ag/mL anti-ADAM28 antibody, and the media (800 AL/lane) were subjected to immunoblotting with anti- IGFBP-3 antibody specific to the COOH-terminal domain of IGFBP-3 (0.2 Materials and Methods Ag/mL; Santa Cruz Biotechnology, Inc., Santa Cruz, CA). Inhibitor activity of Clinical samples and histology. Fresh tissue samples were resected KB-R7785 against ADAM species including ADAM28 was previously from patients with primary breast carcinoma (34 cases) who underwent reported (8, 13). Inhibition of ADAM28 activity with anti-ADAM28 antibody surgery at Keio University Hospital, Tokyo, Japan. Control nonneoplastic (297-2F3) was shown in an assay of IGFBP-3 degradation by ADAM28s (data breast tissues (16 cases) were obtained from sites remote from the not shown). carcinomas. All tumor tissues were obtained at primary resection, and none Immunoblotting analyses were also done using the human breast car- of the patients had been subjected to chemotherapy or radiation therapy cinoma cell lines MDA-MB231 and MCF-7. After synchronization and growth before surgery. The samples were snap-frozen immediately after surgical arrest, cells were treated with 1 Amol/L KB-R7785, 5 Ag/mL anti-ADAM28 removal and stored at À80jC. Human breast carcinomas were classified antibody (297-2F3), or 100 Amol/L aprotinin (Sigma-Aldrich) 30 minutes based on the standard criteria of WHO International Classification of Breast before stimulation with 100 ng/mL IGF-I (Sigma-Aldrich) in the presence of Tumors (21). The 34 cases of carcinomas included invasive ductal each agent for 24 hours, and culture media were subjected to immunoblotting carcinomas (32 cases) and invasive lobular carcinomas (2 cases). Informed with anti-ADAM28 antibody or anti-IGFBP-3 antibody as described above. consent for experimental use of the surgical samples was obtained from Inhibition of IGFBP-3 degradation by the treatments was analyzed by each patient according to institutional ethical guidelines. densitometry using NIH Image 1.63. For analysis of IGF-I cell signaling, Reverse transcription-PCR and real-time quantitative PCR. Total supernatants of the cell homogenates (10 Ag/lane) were subjected to RNA was isolated from frozen sections of breast carcinoma and nonneo- immunoblotting with anti–phospho-IGF type I receptor (p-IGF-IR) antibody plastic control breast tissues and evaluated with Agilent 2100 Bioanalyzer (0.2 Ag/mL; Cell Signaling Co., Beverly, MA), anti-IGF-IR antibody (0.2 Ag/mL; (Agilent Technologies,
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