Inhibition of tumor growth by antibody to ADAMTS1 in mouse xenografts of breast cancer

Division of Breast and Endocrine Surgery, Department of Surgery, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.
Anticancer research (Impact Factor: 1.83). 11/2011; 31(11):3839-42.
Source: PubMed


A disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS1), a member of the ADAMTS family of proteases, is involved in the shedding of epidermal growth factor (EGF)-like ligands such as amphiregulin, which activate the EGF receptor. Since ADAMTS1 has been implicated in aggressive breast carcinogenesis, we examined potential antitumor effects of antibody to ADAMTS1 in a mouse model of breast cancer.
BALB/c female mice were inoculated with syngenic 4T1 breast cancer cells and treated with anti-ADAMTS1 antibody or control IgG. Tumor volume and weight were evaluated.
Mouse 4T1 cells expressed ADAMTS1 and its substrates amphiregulin and heparin-binding EGF. Treatment with antibody to ADAMTS1 inhibited tumor growth without any adverse effects.
ADAMTS1 could be a promising molecular target for immunotherapy of breast cancer.

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    • "Many studies have highlighted its functional activity during tumorigen - ic transformation ( Bonuccelli et al . , 2009 ; Choi et al . , 2008 ; Gustavsson et al . , 2008 , 2009 ; Hirano et al . , 2011 ; Ifon et al. , 2005 ; Tan et al. , 2013 ; Kohno et al. , 2010 ; Kuno et al. , 2004 ; Lind et al. , 2006 ; Liu et al. , 2006 ; Masui et al . , 2001 ; Ricciardelli et al . , 2011 ; Rocks et al . , 2008a , b ; Tyan et al . , 2012 ; Yegnasubramanian et al . , 2011 ) . ADAMTS1 dysregulation is linked to the most commonly diagnosed cancers ."
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    ABSTRACT: ADAM metallopeptidase with thrombospondin type I motif, 1 (ADAMTS1) that has both antiangiogenic and aggrecanase activity was dysregulated in many pathophysiologic circumstances. However, there is limited information available on the transcriptional regulation of ADAMTS1 gene. Therefore, this study mainly aimed to identify regulatory regions important for the regulation of ADAMTS1 gene under normoxic and hypoxic conditions in human hepatoma cells (HEP3B). Cultured HEP3B cells were exposed to normal oxygen condition, and Cobalt chloride (CoCl2) induced the hypoxic condition, which is an HIF-1 inducer. The cocl2-induced hypoxic condition led to the induced ADAMTS1 mRNA and protein expression in Hepatoma cells. Differential regulation of SP1 and USF transcription factors on ADAMTS1 gene expression was determined by transcriptional activity, mRNA and protein level of ADAMTS1 gene. Ectopic expression of SP1 and USF transcription factors resulted in the decrease in ADAMTS1 transcriptional activity of all promoter constructs consistent with mRNA and protein level in normoxic condition. However, overexpression of SP1 and USF led to the increase of ADAMTS1 gene expressions at mRNA and protein level in hypoxic condition. On the other hand, C/EBPα transcription factor didn't show any statistically significant effect on ADAMTS1 gene expression at mRNA, protein and transcriptional level under normoxic and hypoxic condition. Copyright © 2015. Published by Elsevier B.V.
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    ABSTRACT: Since it was first characterized in 1997, the ADAMTS (A Disintegrin and Metalloprotease with ThromboSpondin motifs) metalloprotease family has been associated with many physiological and pathological conditions. Of the 19 proteases belonging to this family, considerable attention has been devoted to the role of its first member ADAMTS1 in cancer. Elevated ADAMTS1 promotes pro-tumorigenic changes such as increased tumor cell proliferation, inhibited apoptosis and altered vascularization. Importantly it facilitates significant peritumoral remodeling of the extracellular matrix environment to promote tumor progression and metastasis. However, discrepancy exists, as several studies also depict ADAMTS1 as a tumor suppressor. This article reviews the current understanding of ADAMTS1 regulation and the consequence of its dysregulation in primary cancer and ADAMTS1-mediated pathways of cancer progression and metastasis. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 11/2013; 133(10). DOI:10.1002/ijc.28127 · 5.09 Impact Factor
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    ABSTRACT: Nuclear factor of activated T cells 1 (NFAT1) expression has been associated with increased migratory/invasive properties of mammary tumor-derived cell lines in vitro. It is unknown, however, if NFAT activation actually occurs in breast cancer cases and whether the calcineurin/NFAT pathway is important to mammary tumorigenesis. Using a cohort of 321 diagnostic cases of the major subgroup of breast cancer, we found Cn/NFAT pathway activated in ER(-)PR(-)HER2(-) triple-negative breast cancer subtype, whereas its prevalence is less in other subgroups. Using a small hairpin RNA-based gene expression silencing approach in murine mammary tumor cell line (4T1), we show that not only NFAT1 but also NFAT2 and their upstream activator Cn are essential to the migratory and invasive properties of mammary tumor cells. We also demonstrate that Cn, NFAT1 and NFAT2 are essential to the tumorigenic and metastatic properties of these cells in mice, a phenotype which coincides with increased apoptosis in vivo. Finally, global gene expression analyses identified several NFAT-deregulated genes, many of them being previously associated with mammary tumorigenesis. In particular, we identified the gene encoding a disintegrin and metalloproteinase with thrombonspondin motifs 1, as being a potential direct target of NFAT1. Thus, our results show that the Cn/NFAT pathway is activated in diagnostic cases of breast cancers and is essential to the tumorigenic and metastatic potential of mammary tumor cell line. These results suggest that pharmacological inhibition of the Cn/NFAT pathway at different levels could be of therapeutical interest for breast cancer patients.
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