Development of the new strategy targeting for the RAD51 overexpression mammary tumor

• Project/Area Number: 24780313
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Clinical veterinary science
• Research Institution: Nippon Veterinary and Life Science University
• Principal Investigator: OCHIAI Kazuhiko 日本獣医生命科学大学, 獣医学部, 講師 (30550488)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: イヌ / 乳腺腫瘍 / BRCA2 / RAD51 / 多型 / 乳がん / DNA相同組換え / 乳癌 / 相同組換え / 分子創薬

Outline of Final Research Achievements

Canine BRCA2 and RAD51 genes locus has been associated with mammary tumors in female dogs. The BRCA2 protein is involved in homologous recombination repair via its interaction with RAD51 recombinase, an interaction mediated by 8 BRC repeats. Previous structural analyses of cancer-associated mutations affecting the BRC repeats have shown that the weakening of RAD51’s affinity for even 1 repeat is sufficient to increase breast cancer susceptibility. In this study, we focused on 2 previously reported canine BRCA2 mutations (T1425P and K1435R) in BRC repeat 3 (BRC3), derived from mammary tumor samples. These mutations affected the interaction of canine BRC3 with RAD51, and were considered deleterious. Two BRC3 mutations (K1440R and K1440E), reported in human breast cancer patients, occur at amino acids corresponding to those of the K1435R mutation in dogs.

Research Products

• [Journal Article] Polymorphisms of canine BRCA2 BRC repeats affecting interaction with RAD51. (2015)
  • Author(s): Ochiai, K., Ishiguro-Oonuma, T., Yoshikawa, Y., Udagawa, C., Kato, Y., Watanabe, M., Bonkobara, M., Morimatsu, M., and Omi, T.
  • Journal Title: Biomed. Res. Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A novel gene expression system strongly enhances the anticancer effects of a REIC/Dkk-3-encoding adenoviral vector (2014)
  • Author(s): Watanabe M., Sakaguchi M., Kinoshita R., Kaku H., Ariyoshi Y., Ueki H., Tanimoto R., Ebara S., Ochiai K., Futami J., Li SA., Huang P., Nasu Y., Huh NH., Kumon H
  • Journal Title: Oncology Reports Volume: 31巻 Issue: 3 Pages: 1089-95
  • DOI: 10.3892/or.2013.2958
  • Peer Reviewed
• [Journal Article] Concentration of Radiocesium in the Wild Japanese Monkey (Macaca fuscata) over the First 15 Months after the Fukushima Daiichi Nuclear Disaster. (2013)
  • Author(s): Hayama, S., Nakiri, S., Nakanishi, S., Ishii, N., Uno, T., Kato, T., Konno, F., Kawamoto, Y., Tsuchida, S., Ochiai, K., and Omi, T.
  • Journal Title: PLoS ONE Volume: e68530 Issue: 7 Pages: e68530-e68530
  • DOI: 10.1371/journal.pone.0068530
  • Peer Reviewed
• [Journal Article] Molecular cloning and tumour suppressor function analysis of canine REIC/Dkk-3 in mammary gland tumours (2013)
  • Author(s): Ochiai, K., Watanabe, M., Azakami, D., Michishita, M., Yoshikawa, Y., Udagawa, C., Metheenukul, P., Chahomchuen, T., Aoki, H., Kumon, H., Morimatsu, M., Omi, T.
  • Journal Title: Vet. J Volume: 197(3) Issue: 3 Pages: 769-775
  • DOI: 10.1016/j.tvjl.2013.04.024
  • Peer Reviewed
• [Journal Article] Oral porphyromonas gingivalis translocates to the liver and regulates hepatic glycogen synthesis through the Akt/GSK-3β signaling pathway (2013)
  • Author(s): Ishikawa M, Yoshida K, Okamura H, Ochiai K, Takamura H, Fujiwara N, Ozaki K.
  • Journal Title: Biochimica Biophysica Acta-Molecular Basis of Disease Volume: 1832 Issue: 12 Pages: 2035-2043
  • DOI: 10.1016/j.bbadis.2013.07.012
  • Peer Reviewed
• [Journal Article] Preclinical Safety and Efficacy of in Situ REIC/Dkk-3 Gene Therapy for Prostate Cancer. (2012)
  • Author(s): Kawauchi, K., Watanabe, M., Kaku, H., Huang, P., Sasaki, K., Sakaguchi, M., Ochiai, K., Huh, NH., Nasu, Y., and Kumon, H.
  • Journal Title: Acta Med. Okayama Volume: 66 Pages: 7-16
  • Peer Reviewed
• [Journal Article] Establishment of a PCR analysis method for canine BRCA2 (2012)
  • Author(s): Yoshikawa Y, Morimatsu M, Ochiai K, Okuda K, Taoda T, Chikazawa S, Shimamura A, Omi T, Bonkobara M, Orino K, Watanabe K.
  • Journal Title: BMC Res Notes Volume: (in press) Issue: 1 Pages: 173-173
  • DOI: 10.1186/1756-0500-5-173
  • Peer Reviewed
• [Journal Article] A novel gene expression system for detecting viable bladder cancer cells (2012)
  • Author(s): Hideo Ueki, et al
  • Journal Title: International journal of oncology Volume: 41 Pages: 135-140
  • DOI: 10.3892/ijo.2012.1417
  • Peer Reviewed
• [Journal Article] PKR plays a positive role in osteoblast differentiation by regulating GSK-3 activity through a β-catenin-independent pathway. (2012)
  • Author(s): Yoshida K et al.
  • Journal Title: Molecular and Cellular Endocrinology Volume: 361(1-2) Issue: 1-2 Pages: 99-105
  • DOI: 10.1016/j.mce.2012.03.019
  • Peer Reviewed
• [Journal Article] Effects of the missense mutations in canine BRCA2 on BRC repeat 3 functions and comparative analyses between canine and human BRC repeat 3 (2012)
  • Author(s): Yoshikawa Y, Ochiai K, Morimatsu M, Suzuki Y, Wada S, Taoda T, Iwai S, Chikazawa S, Orino K, Watanabe K
  • Journal Title: PLoS One Volume: 7 Issue: 10 Pages: e45833-e45833
  • DOI: 10.1371/journal.pone.0045833
  • Peer Reviewed
• [Journal Article] Thiol-organosilica Particles Internally Functionalized with Propidium Iodide as a Multicolor Fluorescence and X-Ray Computed Tomography Probe and Application for Non-Invasive Functional Gastrointestinal Tract Imaging. (2012)
  • Author(s): Nakamura, M., Awaad, A., Hayashi, K., Ochiai, K., and Ishimura, K.
  • Journal Title: Chem. Mater. Volume: 24 Issue: 19 Pages: 3772-3779
  • DOI: 10.1021/cm3023677
  • Peer Reviewed
• [Presentation] DNA相同組換えタンパク質RAD51の動物種特異的アミノ酸配列が機能に及ぼす影響の解析 (2014)
  • Author(s): 落合和彦、閑野大輝、宇田川智野、呰上大吾、大沼俊名、吉川泰永、森松正美、近江俊徳
  • Organizer: 第157回日本獣医学会
  • Place of Presentation: 札幌、北海道
  • Year and Date: 2014-09-09 – 2014-09-11
• [Presentation] がん抑制遺伝子REIC/Dkk-3イヌホモログの構造と乳腺腫瘍に対するアポトーシス誘導能の解析 (2013)
  • Author(s): 落合和彦、渡部昌実、宇田川智野、呰上大吾、森松正美、大沼俊名、近江俊徳
  • Organizer: 第156回日本獣医学会学術集会
  • Place of Presentation: 岐阜大学
• [Presentation] ネコのAB式血液型における各抗原の出現頻度について (2013)
  • Author(s): 蒔田莉菜、古関純也、宇田川智野、鄭英和、落合和彦、呰上大吾、盆子原誠、土田修一、近江俊徳
  • Organizer: 第44回日本比較臨床医学会学術大会
  • Place of Presentation: 自然科学研究機構 生理学研究所
• [Presentation] 新規がん治療候補遺伝子REIC/Dkk-3イヌホモログの構造とアポトーシス誘導能の解析 (2013)
  • Author(s): 落合和彦、宇田川智野、呰上大吾、近江俊徳
  • Organizer: 第44回日本比較臨床医学会学術大会
  • Place of Presentation: 自然科学研究機構 生理学研究所
• [Presentation] イヌ乳腺腫瘍関連遺伝子BRCA2のBRC repeat 3に存在するSNPsの頻度および機能に及ぼす影響の検討 (2013)
  • Author(s): 落合和彦、塩入弓絵、染田沙織、大澤有加、宇田川智野、森松正美、吉川泰永、盆子原誠、土田修一、近江俊徳
  • Organizer: 第155回日本獣医学会
  • Place of Presentation: 東京大学
• [Presentation] 放射線治療抵抗性がんに対するRAD51の制御を基軸とした改変型BRCによる新規治療戦略の開発に向けた基礎研究 (2012)
  • Author(s): 落合和彦、森松正美、吉川泰永、宇田川智野、多田尚美、近江俊徳
  • Organizer: 第154回日本獣医学会
  • Place of Presentation: 岩手大学
• [Presentation] イヌ乳腺腫瘍で発見した癌関連遺伝子産物BRCA2における変異BRC repeat 3の機能解析 (2012)
  • Author(s): 吉川泰永、森松正美、落合和彦、相田成一、垰田高広、近澤征史朗、岩井聡美、折野宏一、渡辺清隆
  • Organizer: 第154回日本獣医学会
  • Place of Presentation: 岩手大学
• [Presentation] 動物種間DNA構造解析によって得られたBRCA2の多型配列がRAD51との相互作用に与える影響の検討 (2012)
  • Author(s): 落合和彦、多田尚美、宇田川智野、近江俊徳
  • Organizer: 第21回日本DNA多型学会
  • Place of Presentation: 京都教育文化センター
• [Remarks] 学校法人日本医科大学 知的財産推進センター 研究者紹介
  • URL: http://tlo.nms.ac.jp/outer/kenkyusyashokai/juidaigaku.html