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  • The EMBO Journal (2005) 24, 963 - 973
  • doi:10.1038/sj.emboj.7600588

Published online: 17 February 2005

Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive activities

Yasuhito Onodera1,2, Shigeru Hashimoto1, Ari Hashimoto1, Masaki Morishige1,3, Yuichi Mazaki1, Atsuko Yamada1, Eiji Ogawa4, Masashi Adachi5, Takaki Sakurai4, Toshiaki Manabe4, Hiromi Wada5, Nariaki Matsuura6 and Hisataka Sabe1,2

  1. Department of Molecular Biology, Osaka Bioscience Institute, Suita, Osaka, Japan
  2. Graduate School of Biostudies, Kyoto University, Kyoto, Japan
  3. Department of Neurosurgery, School of Medicine, Oita University, Oita, Japan
  4. Laboratory of Anatomic Pathology, Kyoto University Hospital, Kyoto, Japan
  5. Laboratory of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan
  6. Department of Pathology, School of Allied Health Science, Faculty of Medicine, Osaka University, Suita, Osaka, Japan

Correspondence to:

Hisataka Sabe, Department of Molecular Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan. Tel.: +81 6 6872 4814; Fax: +81 6 6871 6686; E-mail: sabe@obi.or.jp

Received 29 September 2004; Accepted 28 January 2005

Identification of the molecular machinery employed in cancer invasion, but not in normal adult cells, will greatly contribute to cancer therapeutics. Here we found that an ArfGAP, AMAP1/PAG2, is expressed at high levels in highly invasive breast cancer cells, but at very low levels in noninvasive breast cancer cells and normal mammary epithelial cells. siRNA-mediated silencing of AMAP1 effectively blocked the invasive activities. AMAP1 expression in human breast primary tumors also indicated its potential correlation with malignancy. Paxillin and cortactin have been shown to colocalize at invadopodia and play a pivotal role in breast cancer invasion. We found that AMAP1 is also localized at invadopodia, and acts to bridge paxillin and cortactin. This AMAP1-mediated trimeric protein complex was detected only in invasive cancer cells, and blocking this complex formation effectively inhibited their invasive activities in vitro and metastasis in mice. Our results indicate that AMAP1 is a component involved in invasive activities of different breast cancers, and provide new information regarding the possible therapeutic targets for prevention of breast cancer invasion and metastasis.

  • Keywords:

    • AMAP1,
    • breast cancer,
    • cortactin,
    • invasion and metastasis,
    • paxillin