Elucidation of the molecular mechanisms of early breast cancer invasion and metastasis

• Project/Area Number: 23590323
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Hokkaido University
• Principal Investigator: HASHIMOTO Ari 北海道大学, 医学(系)研究科(研究院), 助教 (60390803)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 浸潤 / 転移 / Arf6 / GEP100 / EMT / p53 / 乳癌 / AMAP1 / ArfGEF

Research Abstract

Cancer progression by which epithelial tumor cells acquire a more motile and invasive phenotype has been closely linked to the epithelial-mesenchymal transition (EMT) process. We found that GEP100-Arf6-AMAP1 pathway is important for acquisition of mesenchymal invasive phenotypes of breast cancers and TP53 alterations link to this process. Metabolic pathway regulated by mutant p53 is required for Arf6 activation. The clinical specimens of human breast cancer showed that the expression of GEP100-Arf6-AMAP1 signal correlated with recurrence after radiotherapy. Database analysis also showed that co-incidence of TP53 mutations and the high expression of this signal pathway statistically correlate with poor survival. These results suggest that generation of the Arf6-based mesenchymal invasive pathway by TP53 alterations regulate malignant progression and appears to be crucial for poor prognosis in breast cancer.

Research Products

• [Journal Article] High Level Expression of AMAP1 Protein Correlates with Poor Prognosis and Survival after Surgery of HNSCC Patients (2014)
  • Author(s): Sato H., Hatanaka K.C., Hatanaka Y., Hatakeyama H., Hashimoto A., Matsuno Y., Fukuda S., Sabe H.
  • Journal Title: Cell Commun Signal Volume: 12 Pages: 12-17
  • Peer Reviewed
• [Journal Article] High level expression of AMAP1 protein correlates with poor prognosis and survival after surgery of head and neck squamous cell carcinoma patients. (2014)
  • Author(s): Sato H, Hatanaka KC, Hatanaka Y, Hatakeyama H, Hashimoto A, Matsuno Y, Fukuda S, Sabe H.
  • Journal Title: Cell Commun Signal. Volume: 12 Issue: 1 Pages: 17-17
  • DOI: 10.1186/1478-811x-12-17
  • NAID: 120005438264
  • Peer Reviewed / Open Access
• [Journal Article] Co-overexpression of GEP100 and AMAP1 proteins correlates with rapid local recurrence after breast conservative therapy (2013)
  • Author(s): Kinoshita R., Nam J.M., Ito Y.M., Hatanaka K.C., Hashimoto A., Handa H., OtsukaY., Hashimoto S., Onodera Y., Hosoda M., Onodera S., Shimizu S., Tanaka S., Shirato H., Tanino M., Sabe H.
  • Journal Title: PLoS One Volume: 8
  • NAID: 120005348196
  • Peer Reviewed
• [Journal Article] Co-overexpression of GEP100 and AMAP1 proteins correlates with rapid local recurrence after breast conservative therapy. (2013)
  • Author(s): Kinoshita R, Nam JM, Ito YM, Hatanaka KC, Hashimoto A, Handa H, Otsuka Y, Hashimoto S, Onodera Y, Hosoda M, Onodera S, Shimizu S, Tanaka S, Shirato H, Tanino M, Sabe H.
  • Journal Title: PLoS One. Volume: 8 Issue: 10 Pages: e76791-e76791
  • DOI: 10.1371/journal.pone.0076791
  • NAID: 120005348196
  • Peer Reviewed
• [Journal Article] Rab5c promotes AMAP1-PRKD2 complex formation to enhance1 integrin recycling in EGF-induced cancer invasion (2012)
  • Author(s): Onodera Y., Nam J.M., Hashimoto A., Norman JC, Shirato H, Hashimoto S., Sabe H.
  • Journal Title: J Cell Biol Volume: 197 Pages: 983-996
  • Peer Reviewed
• [Journal Article] Rab5c mediates AMAP1-PRKD2 complexto enhance β1 integrin recycling inEGF-induced cancer invasion (2012)
  • Author(s): Onodera Y., Nam JM., Hashimoto A., Norman JC., Shirato H., Hashimoto S. and Sabe H
  • Journal Title: J.Cell Biol Volume: 197 Issue: 7 Pages: 983-996
  • DOI: 10.1083/jcb.201201065
  • Peer Reviewed
• [Journal Article] Engagement of overexpressed Her2 with GEP100 induces autonomous invasive activities and provides a biomarker for metastases of lung adenocarcinoma (2011)
  • Author(s): Menju T., Hashimoto S., Hashimoto A., Otsuka Y., Handa H., Ogawa E., Toda Y., Wada H., Date H., and Sabe H.
  • Journal Title: PLoS One Volume: 6
  • NAID: 120003464637
  • Peer Reviewed
• [Journal Article] GEP100-Arf6-AMAP1-cortactin pathway frequently used in cancer invasion is activated by VEGFR2 to promote angiogenesis (2011)
  • Author(s): Hashimoto A., Hashimoto S., Ando R., Noda K., Ogawa E., Kotani H., Hirose M., Menju T., Morishige M., Manabe T., Toda Y., Ishida S., and Sabe H.
  • Journal Title: PLoS One Volume: 6
  • NAID: 120003295085
  • Peer Reviewed
• [Journal Article] GEP100-Arf6-AMAP1-cortactin pathway frequently used in cancer invasion is activated by VEGFR2 to promote angiogenesis (2011)
  • Author(s): Hashimoto A., Hashimoto S., Ando R., Noda K., Ogawa E., Kotani H., Hirose M., Menju T., Morishige M., Manabe T., Toda Y., Ishida S. and Sabe H.
  • Journal Title: PLoS One Volume: 6 Issue: 8 Pages: e23359-e23359
  • DOI: 10.1371/journal.pone.0023359
  • NAID: 120003295085
  • Peer Reviewed
• [Journal Article] Engagement of overexpressed Her2 with GEP100 induces autonomous invasive activities and provides a biomarker for metastases of lung adenocarcinoma (2011)
  • Author(s): Menju T., Hashimoto S., Hashimoto A., Otsuka Y., Handa H., Ogawa E., Toda Y., Wada H., Date H. and Sabe H.
  • Journal Title: PLoS One Volume: 6 Issue: 9 Pages: e25301-e25301
  • DOI: 10.1371/journal.pone.0025301
  • NAID: 120003464637
  • Peer Reviewed
• [Presentation] Mechanisms by which p53 alterations generate GEP100-Arf6-AMAP1 pathway as a mesenchymal invasion machinery to be activated by external ligands (2013)
  • Author(s): Hashimoto A., Hashimoto S., Onodera Y., Oikawa T., Oneyama C., Kinoshita R., Nam J.M., Tanino M., Sugino H., Yoshikawa A., Otsuka Y., Handa H., Yoshino M., Sato H., Fukuda S., Tanaka S., Shirato H., Ito Y., Okada M., Sabe H.
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2013-12-04
• [Presentation] Mutant-p53 generates the GEP100-Arf6-AMAP1 pathway to promote breast cancer invasiveness (2013)
  • Author(s): Hashimoto S., Hashimoto A., Oneyama C., Yoshikawa A., Sugino H., Handa H., Yoshino M., Otsuka Y., Onodera Y., Okada M., Sabe H.
  • Organizer: 第86回日本生化学大会
  • Place of Presentation: 横浜
  • Year and Date: 2013-09-12
• [Presentation] Mutant-p53 generates GEP100-Arf6-AMAP1-EPB41L5 pathway externally activated to promote mesenchymal invasion (2013)
  • Author(s): Hashimoto A., Hashimoto S., Oneyama C., Onodera Y., Sugino H., Yoshikawa A., Otsuka Y., Handa H., Okada M., Sabe H.
  • Organizer: The First International Meeting, Epithelial Tubulology
  • Place of Presentation: 札幌
  • Year and Date: 2013-06-23
• [Presentation] Mutant-p53 generates GEP100-Arf6-AMAP1-EPB41L5 pathway externally activated to promote mesenchymal invasion. (2013)
  • Author(s): Hashimoto A., Hashimoto S., Oneyama C., Onodera Y., Sugino H., Yoshikawa A., Otsuka Y., Handa H., Okada M., and Sabe H.
  • Organizer: The First International Meeting, Epithelial Tubulology
  • Place of Presentation: Conference Hall, Hokkaido University（札幌市）
• [Presentation] Mutant-p53 generates the GEP100-Arf6-AMAP1 pathway to promote breast cancer invasiveness. (2013)
  • Author(s): Hashimoto S., Hashimoto A., Oneyama C., Yoshikawa A., Sugino H., Handa H., Yoshino M., Otsuka Y., Onodera Y., Okada M., and Sabe H.
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] Mechanisms by which oncogenic mutant-p53 generates mesenchymal invasive pathway pivotal to a radiation resistance. (2013)
  • Author(s): Sabe H., Hashimoto A., Hashimoto S., Onodera Y., Oikawa T., Nam J.M., Oneyama C., Sugino H., Yoshikawa A., Otsuka Y., Handa H., Yoshino M., and Okada M.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] Mechanisms by which p53 alterations generate GEP100-Arf6-AMAP1 pathway as a mesenchymal invasion machinery to be activated by external ligands. (2013)
  • Author(s): Hashimoto A., Hashimoto S., Onodera Y., Oikawa T., Oneyama C., Kinoshita R., Nam J.M., Tanino M., Sugino H., Yoshikawa A., Otsuka Y., Handa H., Masanao Y., Sato H., Fukuda S., Tanaka S., Shirato H., Ito Y., Okada M., and Sabe H.
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場（神戸市）
• [Presentation] Mutant-p53 generates GEP100-Arf6-AMAP1 pathway to be activated by TGFβ1 and receptor tyrosine kinases to promote cancer invasion. (2012)
  • Author(s): Hashimoto A., Hashimoto S., Yoshikawa A., Sugino H., Handa H., Kinoshita R., Hatanaka K.C., Mikami S., Tanino M., Mito S., Sato H., Otsuka Y., Yoshino H., Kado Y., Nam J.M., Onodera Y., Tanaka S., Shirato H., Sabe H.
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-12
• [Presentation] Mutant-p53 generates GEP100-Arf6-AMAP1 pathway to promote breast cancer cell invasiveness in response to TGFβ1 (2012)
  • Author(s): Hashimoto A., Hashimoto S., Yoshikawa A., Sugino H., Handa H., Mito S., Sato H., Otsuka Y., Yoshino H., Nam J.M., Onodera Y., Sabe H.
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-20
• [Presentation] MUTANT-p53 GENERATES GEP100-Arf6-AMAP1 PATHWAY TO PROMOTE BREAST CANCER CELL INVASIVENESS IN RESPONSE TO TGFβ1 (2012)
  • Author(s): Hashimoto A., Hashimoto S., Yoshikawa A., Sugino H., Handa H., Mito S., Sato H., Otsuka Y., Yoshino H., Nam J.M., Onodera Y., Sabe H.
  • Organizer: The31th Sapporo International Cancer Symposium
  • Place of Presentation: 札幌
  • Year and Date: 2012-06-23
• [Presentation] 変異p53はArf6活性化経路を介した浸潤獲得形質に必須である (2012)
  • Author(s): 橋本あり, 佐邊壽孝
  • Organizer: 第4回シグナルネットワーク研究会
  • Place of Presentation: 大阪
  • Year and Date: 2012-05-18
• [Presentation] RTKs-GEP100-Arf6-AMAP1 pathway mediates cancerous EMT in response to mutant p53 and TGFβ1 signaling (2012)
  • Author(s): Hisataka Sabe, Ari Hashimoto, Hirokazu Sugino, Ayumu Yoshikawa, Yutaro Otsuka, Haruka Handa, Sizuka Mito, Hiroki Sato, Jin-Min Nam, Yasuhito Onodera and Shigeru Hashimoto
  • Organizer: 第8回OOTR年次学会
  • Place of Presentation: ウェスティン都ホテル京都（京都市）
• [Presentation] 変異p53はArf6活性化経路を介した浸潤獲得形質に必須である (2012)
  • Author(s): 橋本あり、佐邊壽孝
  • Organizer: 第4回シグナルネットワーク研究会
  • Place of Presentation: 大阪大学微研ホール（吹田市）
• [Presentation] EZH2 regulates breast cancer invasiveness through GEP100-Arf6-AMAP1 signaling pathway (2012)
  • Author(s): Hirokazu Sugino, Shigeru Hashimoto, Ari Hashimoto, Ayumu Yoshikawa, Haruka Handa, Sizuka Mito, Hisataka Sabe
  • Organizer: 第45回日本発生生物学会・第64回日本細胞生物学会合同大会
  • Place of Presentation: 神戸国際会議場（神戸市）
• [Presentation] EZH2-mediated downregulation of miR-203 generates the ARF6-AMAP1 pathway pivotal for breast cancer invasiveness (2012)
  • Author(s): Hirokazu Sugino, Shigeru Hashimoto, Ari Hashimoto, Ayumu Yoshikawa, Haruka Handa, Hisataka Sabe
  • Organizer: Beatson International Cancer Conference2012 "Membrane dynamics in cancer"
  • Place of Presentation: Beatson Institute (UK)
• [Presentation] MUTANT-p53 GENERATES GEP100-Arf6-AMAP1 PATHWAY TO PROMOTE BREAST CANCER CELL INVASIVENESS IN RESPONSE TO TGFβ1 (2012)
  • Author(s): Ari Hashimoto, Shigeru Hashimoto, Ayumu Yoshikawa, Hirokazu Sugino, Haruka Handa, Sizuka Mito, Hiroki Sato, Yutaro Otsuka, Hinako Yoshino, Jin-Min Nam, Yasuhito Onodera and Hisataka Sabe
  • Organizer: 第31回札幌国際がんシンポジウム2012
  • Place of Presentation: 北海道大学（札幌市）
• [Presentation] Mutant-p53 generates GEP100-Arf6-AMAP1 pathway to promote breast cancer cell invasiveness in response to TGFβ1 (2012)
  • Author(s): Ari Hashimoto, Shigeru Hashimoto, Ayumu Yoshikawa, Hirokazu Sugino, Haruka Handa, Sizuka Mito, Hiroki Sato, Yutaro Otsuka, Hinako Yoshino, Jin-Min Nam, Yasuhito Onodera and Hisataka Sabe
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（札幌市）
• [Presentation] EZH2-mediated downregulation of miR-203 generates the Arf6-AMAP1 pathway pivotal for breast cancer invasiveness (2012)
  • Author(s): Hirokazu Sugino,Shigeru Hashimoto, Ari Hashimoto, Yasuhito Onodera, Ayumu Yoshikawa, Yutaro Otsuka, Shizuka Mito, Haruka Handa, Hiroki Sato and Hisataka Sabe
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（（札幌市）
• [Presentation] GAB1 links c-Met signaling with GEP100-Arf6-AMAP1 pathway to promote breast cancer invasiveness (2012)
  • Author(s): Ayumu Yoshikawa, Shigeru Hashimoto, Ari Hashimoto, Hirokazu Sugino, Yutaro Otsuka, Shizuka Mito, Haruka Handa and Hisataka Sabe
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（札幌市）
• [Presentation] beta1 integrin recycling via AMAP1-PRKD2 complex regulated by small GTPases in cancer invasion (2012)
  • Author(s): Yasuhito Onodera, Jin-Min Nam, Ari Hashimoto, Hiroki Shirato, Shigeru Hashimoto and Hisataka Sabe
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（（札幌市）
• [Presentation] Mutant-p53 generates the GEP100-Arf6-AMAP1 pathway to be activated by TGFβ1 and receptor tyrosine kinases to promote cancer invasion (2012)
  • Author(s): Ari Hashimoto, Shigeru Hashimoto, Ayumu Yoshikawa et al
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場（福岡市）
• [Presentation] EZH2 suppresses miR-203 expression to promote cancer invasion (2012)
  • Author(s): Shigeru Hashimoto, Hirokazu Sugino, Ari Hashimoto, Ayumu Yoshikawa, Yutaro Otsuka, Masanao Yoshino, Haruka Handa and Hisataka Sabe
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場（福岡市）
• [Presentation] Tissue morphogenesis by co-operative regulation of cellular proliferation and migration and diseases due to its breakdown (2012)
  • Author(s): Yasuhito Onodera, Jin-Min Nam, Ari Hashimoto, Mina Bissell, Shigeru Hashimoto, Hisataka Sabe
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場（福岡市）
• [Presentation] Mutant p53 is essential for TGFβ1-induced breast cancer cell invasion via activation of GEP100-Arf6-AMAP1 pathway (2011)
  • Author(s): Hashimoto A. , Hashimoto S., Otsuka Y., Yoshikawa A., Sugino H., Handa H., Sato H., Nam J.M., Shirato H., Fukuda S., Onodera Y., Sabe H.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-15
• [Presentation] Mutant p53 is essential for TGFβ1-induced breast cancer cell invasiveness via activation of GEP100-Arf6-AMAP1 pathway (2011)
  • Author(s): Hashimoto A., Hashimoto S., Otsuka Y., Yoshikawa A., Sugino H., Handa H., Nam J.M., Sato H., Fukuda S., Onodera Y., Sabe H.
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-03
• [Presentation] HGFR/c-Met-mediated activation of GEP100-Arf6-AMAP1 pathway is an integral part for TGFβ-induced cancerous EMT and invasiveness (2011)
  • Author(s): Hashimoto A., Hashimoto S., Otsuka Y., Handa H., Sato H., Sugino H., Yoshikawa A., Umemoto T., Onodera Y., Fukuda S., Sabe H.
  • Organizer: 第63回日本細胞生物学会大会
  • Place of Presentation: 札幌
• [Presentation] HGFR/c-Met-mediated activation of GEP100-Arf6-AMAP1 pathway is an integral part for TGFβ-induced cancerous EMT and invasiveness (2011)
  • Author(s): Hashimoto A., Hashimoto S., Otsuka Y., Sato H., Sugino H., Yoshikawa A., Umemoto T., Onodera Y., Fukuda S., and Sabe H.
  • Organizer: 第63回 日本細胞生物学会大会
  • Place of Presentation: 北海道大学（札幌市）
• [Presentation] Mutant p53 is essential for TGFβ1-induced breast cancer cell invasiveness via activation of GEP100-Arf6-AMAP1 pathway (2011)
  • Author(s): Hashimoto A., Hashimoto S., Otsuka Y., Yoshikawa A., Sugino H., Handa H., Nam J.M., Sato H., Fukuda S., Onodera Y., and Sabe H.
  • Organizer: 第70回 日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県）
• [Presentation] Mutant p53 is essential for TGFβ1-induced breast cancer cell invasion via activation of GEP100-Arf6-AMAP1 pathway (2011)
  • Author(s): Hashimoto A., Hashimoto S., Otsuka Y., Yoshikawa A., Sugino H., Handa H., Sato H., Nam J.M., Shirato H., Fukuda S., Onodera Y., and Sabe H.
  • Organizer: 第34回 日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Book] Ras superfamily small G proteins: Biology and Mechanisms (2014)
  • Author(s): Hashimoto S., Hashimoto A., Sugino H., Yoshikawa A., Handa H., Yoshino M., Otsuka Y., and Sabe H.
  • Total Pages: 20
  • Publisher: Springer Book
• [Book] EMT-基礎的観点から,(戸井雅和編:乳癌レビュー2012) (2012)
  • Author(s): 橋本あり, 杉野弘和, 橋本茂, 佐邊壽孝
  • Publisher: メディカルレビュー社
• [Book] 「EMT-基礎的観点から」乳癌レビュー2012 (2012)
  • Author(s): 橋本あり、杉野弘和、橋本茂、佐邊壽孝
  • Total Pages: 7
  • Publisher: メディカルレビュー社
• [Book] 「局所浸潤モデルーがんの浸潤転移に関わる分子装置の解析法」『疾患モデルの作製と利用ーがん』 (2012)
  • Author(s): 橋本あり、橋本茂、佐邊壽孝
  • Total Pages: 11
  • Publisher: 株式会社エル・アイ・シー
• [Book] 乳癌レビュー2012 EMT-基礎的観点から (2011)
  • Author(s): 橋本 あり、杉野 弘和、橋本 茂、佐邊 壽孝
  • Total Pages: 7
  • Publisher: メディカルレビュー社
• [Book] 局所浸潤モデル-がんの浸潤転移に関わる分子装置の解析法(中村卓郎編:疾患モデルの作製と利用)
  • Author(s): 橋本あり, 橋本茂, 佐邊壽孝
  • Publisher: エル・アイ・シー(株)
• [Remarks]
  • URL: http://www.hucc.hokudai.ac.jp/~g21001/index.html
• [Remarks] 北海道大学 大学院医学研究科 生化学講座 分子生物学分野
  • URL: http://www.hucc.hokudai.ac.jp/~g21001/index.html
• [Remarks] 北海道大学 大学院医学研究科 生化学講座 分子生物学分野
  • URL: http://www.hucc.hokudai.ac.jp/~g21001/index.html
• [Patent(Industrial Property Rights)] 乳癌乳房温存療法後の局所再発リスクの予測に用いるための診断薬並びに予測方法 (2013)
  • Inventor(s): 佐邊壽孝, 橋本 茂, 橋本あり, 小野寺康仁, 白土博樹, 木下留美子
  • Industrial Property Rights Holder: 北海道大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-03-04
  • Overseas
• [Patent(Industrial Property Rights)] 放射線治療増強薬及び放射線抵抗性癌の治療方法 (2013)
  • Inventor(s): 佐邊壽孝, 小野寺康仁, Nam Jin Min, 橋本 茂, 橋本あり
  • Industrial Property Rights Holder: 北海道大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-148970
  • Filing Date: 2013-07-17
  • Overseas
• [Patent(Industrial Property Rights)] 放射線治療増強薬及び放射線抵抗性癌の治療方法 (2013)
  • Inventor(s): 佐邊壽孝、小野寺康仁、Nam Jin Min、橋本 茂、橋本あり
  • Industrial Property Rights Holder: 佐邊壽孝、小野寺康仁、Nam Jin Min、橋本 茂、橋本あり
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-07-17