A novel mechanism of breast carcinogenesis caused by transcription-coupled DNA damage

• Project/Area Number: 24590388
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Aichi Cancer Center Research Institute (2014); Kumamoto University (2012-2013)
• Principal Investigator: KUWAHARA Kazuhiko 愛知県がんセンター(研究所), 腫瘍免疫学部, 室長 (10263469)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 非遺伝性散発性乳癌 / DNA傷害 / 乳癌 / ＤＮＡ傷害 / エストロゲン / マウスモデル / mRNA核外輸送

Outline of Final Research Achievements

The occurrence of sporadic breast cancers is involved in long-term exposure of estrogen, which induces DNA damages in the epithelial cells of mammary glands. Estrogen stimulation induced rigorous DNA damages in ganp-depleted MCF7, suggesting that these damages is asoociated with abnormal development of mammary glands in mammary-specific ganp-deficient mice. GANP may be a tumor suppressive factor in mammary gland epithelia. Accordingly, it has been proved that low expression of GANP is an indicator of poor patients' prognosis in sporadic breast cancers.

Research Products

• [Journal Article] JNK Regulatory Molecule G5PR Induces IgG Autoantibody-Producing Plasmablasts from Peritoneal B1a Cells. (2015)
  • Author(s): Kitabatake M, Soma M, Zhang T, Kuwahara K, Fukushima Y, Nojima T, Kitamura D, Sakaguchi N.
  • Journal Title: J Immunol. Volume: 194 Issue: 4 Pages: 1480-1488
  • DOI: 10.4049/jimmunol.1401127
  • Peer Reviewed / Open Access
• [Journal Article] Pcid2 inactivates developmental genes in human and mouse embryonic stem cells to sustain their pluripotency by modulation of Eid1 stability. (2014)
  • Author(s): Buqing Ye, Zhonghua Dai, Benyu Liu, Rui Wang, Chong Li, Guanling Huang, Shuo Wang, Pengyan Xia, Xuan Yang, Kazuhiko Kuwahara, Nobuo Sakaguchi, Zusen Fan
  • Journal Title: Stem Cells Volume: 32 Pages: 623-635
  • Peer Reviewed
• [Journal Article] Efficacy of anti-CD47 antibody-mediated phagocytosis with macrophages against primary effusion lymphoma. (2014)
  • Author(s): Goto H, Kojima Y, Matsuda K, Kariya R, Taura M, Kuwahara K, Nagai H, Katano H, Okada S.
  • Journal Title: The European Journal of Cancer Volume: 50(10) Issue: 10 Pages: 1836-46
  • DOI: 10.1016/j.ejca.2014.03.004
  • Peer Reviewed
• [Journal Article] Histopathological evaluation of the diversity of cells susceptible to H5N1 virulent avian influenza virus (2013)
  • Author(s): Ogiwara H, Yasui F, Munekata K, Takagi-Kamiya A, Munakata T, Nomura N, Shibasaki F, Kuwahara K, Sakaguchi N, Sakoda Y, Kida H, Kohara M
  • Journal Title: Am. J. Pathol Volume: 184 Issue: 1 Pages: 171-183
  • DOI: 10.1016/j.ajpath.2013.10.004
  • Peer Reviewed / Open Access
• [Journal Article] Antitumor Impact of p14ARF on Gefitinib-Resistant Non-Small Cell Lung Cancers. (2013)
  • Author(s): Saito K, Takigawa N, Ohtani N, Iioka H, Tomita Y, Ueda R, Fukuoka J, Kuwahara K, Ichihara E, Kiura K, Kondo E.
  • Journal Title: Molecule Cancer Therapeutics Volume: 12 Issue: 8 Pages: 1616-1628
  • DOI: 10.1158/1535-7163.mct-12-1239
  • Peer Reviewed
• [Journal Article] CA-S27 : a novel Lewis a associated carbohydrate epitope is diagnostic and prognostic for cholangiocarcinoma (2013)
  • Author(s): Silsirivanit A, Araki N, Wongkham C, Vaeteewoottacharn K, Pairojkul C, Kuwahara K, Narimatsu Y, Sawaki H, Narimatsu H, Okada S, Sakaguchi N, Wongkham S
  • Journal Title: Cancer Sci Volume: 104 Issue: 10 Pages: 1278-1284
  • DOI: 10.1111/cas.12222
  • Peer Reviewed
• [Journal Article] Broad-spectrum detection of h5 subtype influenza a viruses with a new fluorescent immunochromatography system (2013)
  • Author(s): Sakurai A, Takayama K, Nomura N, Munakata T, Yamamoto N, Tamura T, Yamada J, Hashimoto M, Kuwahara K, Sakoda Y, Suda Y, Kobayashi Y, Sakaguchi N, Kida H, Kohara M, Shibasaki F
  • Journal Title: PLoS One Volume: 8 Issue: 11 Pages: e76753-e76753
  • DOI: 10.1371/journal.pone.0076753
  • Peer Reviewed
• [Journal Article] Breast cancers with high DSS1 expression that potentially maintains BRCA2 stability have poor prognosis in the relapse-free survival (2013)
  • Author(s): Rezano A, Kuwahara K, Yamamoto-Ibusuki M, Kitabatake M, Moolthiya P, Phimsen S, Suda T, Tone S, Yamamoto Y, Iwase H, Sakaguchi N
  • Journal Title: BMC Cancer Volume: 13 Issue: 1 Pages: 562-562
  • DOI: 10.1186/1471-2407-13-562
  • Peer Reviewed
• [Journal Article] Dynamic appearance of antigenic epitopes effective for viral neutralization during membrane fusion initiated by interactions between HIV-1 envelope proteins and CD4/CXCR4 (2012)
  • Author(s): Toda T, et al
  • Journal Title: Immunobiology Volume: (印刷中) Issue: 9 Pages: 864-872
  • DOI: 10.1016/j.imbio.2011.12.007
  • Peer Reviewed
• [Journal Article] Selective cell death of p53-insufficient cancer cells is induced by knockdown of the mRNA export molecule GANP (2012)
  • Author(s): Phimsen S, et al
  • Journal Title: Apoptosis Volume: (印刷中) Issue: 7 Pages: 679-690
  • DOI: 10.1007/s10495-012-0711-8
  • Peer Reviewed
• [Journal Article] Transgenic overexpression of G5PR that is normally augmented in centrocytes impairs the enrichment of high-affinity Ag-specific B cells, increases peritoneal B-1a cells, and induces autoimmunity in aged female mice. (2012)
  • Author(s): Masahiro Kitabatake
  • Journal Title: Journal of Immunology Volume: 189 Pages: 1193-1201
  • Peer Reviewed
• [Journal Article] Lyn signaling to upregulate GANP is critical for the survival of high-affinity B cells in germinal centers of lymphoid organs. (2012)
  • Author(s): Kazuhiko Kuwahara
  • Journal Title: Journal of Immunology Volume: 189 Pages: 3472-3479
  • Peer Reviewed
• [Presentation] 散発性乳癌におけるDSS1高発現はBRCA2の発現変化とは無関係に患者予後因子となる (2014)
  • Author(s): 桑原一彦、岩瀬弘敬、葛島清隆、阪口薫雄
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] The role of mammalian TREX2 complex in sporadic breast cancers (2014)
  • Author(s): Kazuhiko Kuwahara
  • Organizer: BIBMC 2014
  • Place of Presentation: Bandung, Indonesia
  • Year and Date: 2014-09-18 – 2014-09-19
  • Invited
• [Presentation] BRCA2安定化因子DSS1の発現上昇は非遺伝性散発性乳癌における予後因子である (2014)
  • Author(s): 桑原一彦、阪口薫雄
  • Organizer: 日本がん分子標的治療学会学術集会
  • Place of Presentation: TKPガーデンシティ仙台
  • Year and Date: 2014-06-25 – 2014-06-27
• [Presentation] 乳癌発症におけるmRNA核外輸送複合体分子GANP異常の関与 (2013)
  • Author(s): 桑原一彦、阪口薫雄
  • Organizer: 日本がん分子標的治療学会
  • Place of Presentation: 国立京都国際会館
• [Presentation] 乳癌発症におけるTREX2複合体の役割 (2013)
  • Author(s): 桑原一彦、岩瀬弘敬、阪口薫雄
  • Organizer: 日本癌学会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Protein phosphatase subunit G5PR regulates the plasmablast differentiation and autoantibody production of peritoneal B-1a cells (2013)
  • Author(s): 北畠正大、張田力、桑原一彦、阪口薫雄
  • Organizer: 日本免疫学会
  • Place of Presentation: 幕張メッセ
• [Presentation] Mammalian Leng8 carrying a Sac3/GANP homologous region upregulated in germinal center B cells is involved in regulation of BCR-mediated proliferation (2013)
  • Author(s): 桑原一彦、北畠正大、北村大介、阪口薫雄
  • Organizer: 日本免疫学会
  • Place of Presentation: 幕張メッセ
• [Presentation] siGanpによるp53変異悪性腫瘍特異的な腫瘍増殖阻止 (2012)
  • Author(s): 桑原一彦
  • Organizer: 日本がん分子標的学会
  • Place of Presentation: 北九州市西日本総合展示場
• [Presentation] 高親和性B細胞制御と抗癌単クローン抗体 (2012)
  • Author(s): 阪口薫雄
  • Organizer: 日本がん免疫学会
  • Place of Presentation: 北海道大学学術交流会館
• [Presentation] Ganp siRNAはp53不活性型悪性腫瘍に選択的に細胞死を誘導することができる (2012)
  • Author(s): 桑原一彦
  • Organizer: 日本癌学会
  • Place of Presentation: ロイトン札幌
• [Presentation] 乳腺上皮細胞におけるエストロゲンが誘導するDNA損傷においてGANPは重要な役割を果たす (2012)
  • Author(s): 阪口薫雄
  • Organizer: 日本癌学会
  • Place of Presentation: ロイトン札幌
• [Presentation] Lyn-mediated signaling to GANP upregulation is essential for persistence of high-affinity antigen-specific B-cells during immune response (2012)
  • Author(s): 桑原一彦
  • Organizer: 日本免疫学会
  • Place of Presentation: 神戸国際会議場
• [Presentation] Survival of antigen-driven germinal center B-cell is controlled by centrocyte-associated expression of apoptosis-regulator G5PR (2012)
  • Author(s): 北畠正大
  • Organizer: 日本免疫学会
  • Place of Presentation: 神戸国際会議場
• [Book] 免疫・アレルギー疾患イラストレイテッド (2013)
  • Author(s): 桑原一彦、阪口薫雄
  • Publisher: 羊土社
• [Patent(Industrial Property Rights)] 高病原性トリインフルエンザに対する抗体 (2012)
  • Inventor(s): 阪口薫雄、桑原一彦、小原道法、芝崎太
  • Industrial Property Rights Holder: 熊本大学、東京都医学研究機構東京都臨床医学総合研究所
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-278228
  • Filing Date: 2012-12-20