Functional analysis of TREX2 complex in the development and malignant progression of sporadic breast cancers

• Project/Area Number: 15K10083
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Niigata University (2016-2017); Aichi Cancer Center Research Institute (2015)
• Principal Investigator: Kuwahara Kazuhiko 新潟大学, 医歯学系, 講師 (10263469)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 乳癌 / 転写共役型DNA傷害 / 乳癌発症機構 / 転写共役型ＤＮＡ傷害

Outline of Final Research Achievements

We found that the deficiency of GANP, a member of TREX2 complex, resulted in the spontaneous development of mammary gland tumors in mice. To examine if GANP insufficiency is associated with human breast cancer development, we identified several SNPs of ganp and demonstrated one of the SNPs at the ganp locus was significantly associated with reduced breast cancer risk and longer disease-free survival in breast cancer patients. These results suggest that GANP is critical for the occurrence and progression of sporadic breast cancer. In addition, spliced variants in ganp mRNA lacking HAT enzymatic activity was observed in human breast cancer cases, suggesting that the development of sporadic breast cancers is involved in HAT activity of GANP.

Research Products

• [Int'l Joint Research] パジャジャラン大学医学部(インドネシア)
• [Int'l Joint Research] University of Florida(米国)
• [Journal Article] Classic Hodgkin lymphoma with osseous involvement mimicking Langerhans cell histiocytosis in a child. (2018)
  • Author(s): Kazuhiko Kuwahara, Ko Kudo, Akiko Yashima-Abo, Kosuke Katayama, Keiko Kojima, Kiyoshi Tone, Etsuro Ito, Atsuko Nakazawa, Hideto Iwafuchi, Akira Kurose.
  • Journal Title: Human Pathology Volume: 印刷中
  • Peer Reviewed
• [Journal Article] GANP protein encoded on human chromosome 21/mouse chromosome 10 is associated with resistance to mammary tumor development. (2016)
  • Author(s): Kuwahara K, Yamamoto-Ibusuki M, Zhang Z, Phimsen S, Gondo N, Yamashita H, Takeo T, Nakagata N, Yamashita D, Fukushima Y, Yamamoto Y, Iwata H, Saya H, Kondo E, Matsuo K, Takeya M, Iwase H, Sakaguchi N.
  • Journal Title: Cancer Sci Volume: in press Issue: 4 Pages: 469-477
  • DOI: 10.1111/cas.12883
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunodominant SARS coronavirus epitopes in humans elicited both enhancing and neutralizing effects on infection in non-human primates. (2016)
  • Author(s): Wang Q, Zhang L, Kuwahara K, Li L, Liu Z, Li T, Zhu H, Liu J, Xu Y, Xie J, Morioka H, Sakaguchi N, Qin C, Liu G.
  • Journal Title: ACS Infectious Diseases Volume: in press Issue: 5 Pages: 361-376
  • DOI: 10.1021/acsinfecdis.6b00006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Presentation] TREX2 complex as a molecular target to sensitize anti-cancer agents (2017)
  • Author(s): Kazuhiko Kuwahara, Eisaku Kondo
  • Organizer: 第106回日本病理学会総会
• [Presentation] 生体内腫瘍におけるＲーＬｏｏｐ形成亢進の特徴と意義 (2017)
  • Author(s): 栗田菜花、桑原一彦、近藤英作
  • Organizer: 第14回日本病理学会カンファレンス
• [Presentation] Forced reduction of TREX2 complex highly sensitizes chemotherapy to breast cancer cells (2017)
  • Author(s): Kazuhiko Kuwahara, Eisaku Kondo
  • Organizer: 第21回日本がん分子標的治療学会
• [Presentation] Depletion of TREX2 components, which is related to R-loop accumulation, sensitizes chemotherapy to breast cancer cells (2017)
  • Author(s): Kazuhiko Kuwahara, Eisaku Kondo
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Identification of ganp SNPs affecting both the development and malignant progression in human sporadic breast cancers. (2016)
  • Author(s): Kazuhiko Kuwahara, Hidemi Ito, Haruru Kotani, Nobuyuki Tsunoda, Kiyotaka Kuzushima, Hiroji Iwata, Masato Nagino, Hideo Tanaka, and Keitaro Matsuo
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] 乳癌細胞においてTREX2複合体構成分子は薬剤感受性誘導の標的となる (2016)
  • Author(s): 桑原一彦
  • Organizer: 日本がん分子標的治療学会
  • Place of Presentation: 別府国際コンベンションセンター（大分県別府市）
  • Year and Date: 2016-05-30
• [Presentation] Molecular epidemiological studies of germinal center-associated nuclear protein (ganp) in the development of human sporadic breast cancers. (2016)
  • Author(s): Kazuhiko Kuwahara, Hidemi Ito, Kiyotaka Kuzushima, Hiroji Iwata, Hideo Tanaka, and Keitaro Matsuo
  • Organizer: AACR Annual Meeting 2016
  • Place of Presentation: Ernest N. Morial Convention Center（米国・ニューオリンズ）
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] DSS1 depletion is a promising strategy increasing chemosensitivity possibly independent of BRCA2 expression. (2015)
  • Author(s): Naomi Gondo, Andri Rezano, Kiyotaka Kuzushima, Hiroji Iwata and Kazuhiko Kuwahara
  • Organizer: The 38th San Antonio Breast Cancer Symposium (SABCS 2015)
  • Place of Presentation: Henry B. Gonzalez Convention Center（米国・サンアントニオ）
  • Year and Date: 2015-12-08
  • Int'l Joint Research
• [Presentation] Molecular epidemiological studies of ganp in the development of sporadic breast cancers. (2015)
  • Author(s): Kazuhiko Kuwahara, Hidemi Ito, Hirotaka Iwase, Kiyotaka Kuzushima, Hiroji Iwata, Hideo Tanaka, and Keitaro Matsuo
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2015-10-08