ADAM28 is overexpressed in human breast carcinomas

Implications for carcinoma cell proliferation through cleavage of insulin-like growth factor binding protein-3

Yoko Mitsui, Satsuki Mochizuki, Takahide Kodama, Masayuki Shimoda, Takashi Ohtsuka, Takayuki Shiomi, Miyuki Chijiiwa, Tadashi Ikeda, Masaki Kitajima, Yasunori Okada

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

A disintegrin and metalloproteinases (ADAMs) are involved in various biological events including cell adhesion, cell fusion, membrane protein shedding, and proteolysis. In the present study, our reverse transcription-PCR analysis showed that among the 12 different ADAM species with a putative metalloproteinase motif, prototype membrane-anchored ADAM28m and secreted-type ADAM28s are selectively expressed in human breast carcinoma tissues. By real-time quantitative PCR, their expression levels were significantly higher in carcinomas than in nonneoplastic breast tissues. In situ hybridization, immunohistochemistry, and immunoblotting analyses indicated that ADAM28 is predominantly expressed in an active form by carcinoma cells within carcinoma tissues. A direct correlation was observed between mRNA expression levels and proliferative activity of the carcinoma cells. Treatment of ADAM28-expressing breast carcinoma cells (MDA-MB231) with insulin-like growth factor-I (IGF-I) increased cell proliferation, cleavage of IGF binding protein (IGFBP)-3, as well as IGF-I cell signaling; these processes were all significantly inhibited by treatment with ADAM inhibitor or anti-ADAM28 antibody. Down-regulation of ADAM28 expression in MDA-MB231 cells with small interfering RNA significantly reduced cell proliferation, IGFBP-3 cleavage, and growth of xenografts in mice. In addition, cleavage of IGFBP-3 in breast carcinoma tissues was correlated with ADAM28 expression levels and inhibited by treatment with ADAM inhibitor or anti-ADAM28 antibody. These results show that ADAM28 is overexpressed in an activated form in human breast carcinoma cells and suggest that ADAM28 is involved in cell proliferation through enhanced bioavailability of IGF-I released from the IGF-I/IGFBP-3 complex by selective IGFBP-3 cleavage in human breast carcinomas.

Original languageEnglish
Pages (from-to)9913-9920
Number of pages8
JournalCancer Research
Volume66
Issue number20
DOIs
Publication statusPublished - 2006 Oct 15

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Insulin-Like Growth Factor Binding Protein 3
Metalloproteases
Disintegrins
Cell Proliferation
Breast Neoplasms
Carcinoma
Insulin-Like Growth Factor I
Anti-Idiotypic Antibodies
Cell Fusion
Immunoblotting
Heterografts
Cell Adhesion
Small Interfering RNA
Biological Availability
Proteolysis
Reverse Transcription
In Situ Hybridization
Real-Time Polymerase Chain Reaction
Membrane Proteins
Breast

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

ADAM28 is overexpressed in human breast carcinomas : Implications for carcinoma cell proliferation through cleavage of insulin-like growth factor binding protein-3. / Mitsui, Yoko; Mochizuki, Satsuki; Kodama, Takahide; Shimoda, Masayuki; Ohtsuka, Takashi; Shiomi, Takayuki; Chijiiwa, Miyuki; Ikeda, Tadashi; Kitajima, Masaki; Okada, Yasunori.

In: Cancer Research, Vol. 66, No. 20, 15.10.2006, p. 9913-9920.

Research output: Contribution to journalArticle

Mitsui, Yoko ; Mochizuki, Satsuki ; Kodama, Takahide ; Shimoda, Masayuki ; Ohtsuka, Takashi ; Shiomi, Takayuki ; Chijiiwa, Miyuki ; Ikeda, Tadashi ; Kitajima, Masaki ; Okada, Yasunori. / ADAM28 is overexpressed in human breast carcinomas : Implications for carcinoma cell proliferation through cleavage of insulin-like growth factor binding protein-3. In: Cancer Research. 2006 ; Vol. 66, No. 20. pp. 9913-9920.
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