Elucidation of estrogen receptor-mediated transcription regulatory systems and downstream signaling pathways in breast cancer and clinical application to cancer management

• Project/Area Number: 26293223
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Saitama Medical University
• Principal Investigator: HORIE KUNIKO 埼玉医科大学, 医学部, 教授 (90261982)
• Co-Investigator(Renkei-kenkyūsha): INOUE SATOSHI 埼玉医科大学, 医学部, 客員教授 (40251251)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2014: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: 乳がん / エストロゲン受容体 / ホルモン治療抵抗性 / 長鎖非コードRNA / マイクロRNA / RNAシーケンス / バイオマーカー / 内科

Outline of Final Research Achievements

Based on high-throughput sequencing using estrogen-sensitive and hormone therapy-refractory model breast cancer cells, we identified several long noncoding RNAs that are transcribed from the vicinity of estrogen receptor binding sites and exhibit estrogen-dependent expression. We found that the siRNA-mediated knockdown of these noncoding RNAs inhibited the growth of breast cancer cells including hormone therapy-refractory types and the growth of breast cancer cell-derived tumors inoculated in nude mice. Based on functional screenings, we identified several relevant factors and microRNAs together with their target genes, which have associations with prognosis of breast cancer patients. Those molecules could be clinically applied to diagnostic and therapeutic targets for breast cancer management.

Research Products

• [Journal Article] Estrogen modulates exercise endurance along with mitochondrial uncoupling protein 3 downregulation in skeletal muscle of female mice. (2016)
  • Author(s): Nagai S, Ikeda K, Horie-Inoue K, Shiba S, Nagasawa S, Takeda S, Inoue S.
  • Journal Title: Biochem Biophys Res Commun Volume: 480 Issue: 4 Pages: 758-784
  • DOI: 10.1016/j.bbrc.2016.10.129
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ABHD2, an androgen target gene, promotes prostate cancer cell proliferation and migration. (2016)
  • Author(s): Obinata D, Takada S, Takayama K, Urano T, Ito A, Ashikari D, Fujiwara K, Yamada Y, Murata T, Kumagai J, Fujimura T, Ikeda K, Horie-Inoue K, Homma Y
  • Journal Title: Eur J Cancer 57 Volume: 57 Pages: 39-49
  • DOI: 10.1016/j.ejca.2016.01.002
  • Peer Reviewed
• [Journal Article] miR-378a-3p modulates tamoxifen sensitivity in breast cancer MCF-7 cells through targeting GOLT1A (2015)
  • Author(s): Ikeda K, Horie-Inoue K, Ueno T, Suzuki T, Sato W, Shigekawa T, Osaki A, Saeki T, Berezikov E, Mano H, Inoue S
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 13170-13170
  • DOI: 10.1038/srep13170
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] MicroRNA-574-3p, identified by microRNA library-based functional screening, modulates tamoxifen response in breast cancer (2015)
  • Author(s): Ujihira T, Ikeda K, Suzuki T, Yamaga R, Sato W, Horie-Inoue K, Shigekawa T, Osaki A, Saeki T, Okamoto K, Takeda S, Inoue S
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 7641-7641
  • DOI: 10.1038/srep07641
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] EBAG9 modulates host immune defense against tumor formation and metastasis by regulating cytotoxic activity of T lymphocytes (2014)
  • Author(s): Miyazaki T, Ikeda K, Horie-Inoue K, Kondo T, Takahashi S, Inoue S
  • Journal Title: Oncogenesis Volume: 3 Issue: 11 Pages: e126-e126
  • DOI: 10.1038/oncsis.2014.40
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Functional shRNA library screening and sequencing-based identification of coding and non-coding RNAs that associate with the biology of hormone refractory cancers. (2016)
  • Author(s): Kuniko Horie
  • Organizer: 第39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、横浜市）
  • Year and Date: 2016-12-02
  • Invited
• [Presentation] ホルモン依存性がんにおける長鎖非コードRNAの役割. (2015)
  • Author(s): 堀江公仁子、池田和博、井上聡
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-02
• [Presentation] A stabilizing factor for mitochondrial respiratory supercomplex assembly facilitates breast tumor growth in hypoxia. (2015)
  • Author(s): Ikeda K, Horie-Inoue K, Inoue S
  • Organizer: EMBO Meeting, Nuclear receptors: From molecules to humans.
  • Place of Presentation: アジャクシオ（コルシカ島、フランス）
  • Year and Date: 2015-09-24
  • Int'l Joint Research
• [Presentation] Integrated analysis identified estrogen-dependent FOXP1 actions on G protein-coupled receptor signaling in breast cancer cells. (2015)
  • Author(s): Horie-Inoue K, Ikeda K, Inoue S
  • Organizer: FASEB Science Research Conferences. Molecular and Systems Integration of Genomic and Nongenomic Steroid Hormone Action.
  • Place of Presentation: ビッグスカイ（モンタナ州、米国）
  • Year and Date: 2015-08-09
  • Int'l Joint Research
• [Presentation] ホルモン応答性長鎖非コードRNAの同定・機能の解明と抗加齢医学への応用. (2015)
  • Author(s): 堀江公仁子、井上聡
  • Organizer: 第15回日本抗加齢医学会総会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-05-30
• [Presentation] Gene regulatory networks mediated by estrogen receptor and forkhead transcription factors in breast cancer (2015)
  • Author(s): Horie-Inoue K, Ikeda K, Inoue S
  • Organizer: Cold Spring Harbor Laboratory Meeting on Systems Biology: Networks
  • Place of Presentation: Cold Spring Habor Laboratory, NY, USA
  • Year and Date: 2015-03-17 – 2015-03-21
• [Presentation] 乳がんの病態進行にかかわるアンチセンス長鎖非コードRNA の同定と機能解析 (2014)
  • Author(s): 堀江公仁子、池田和博、井上聡
  • Organizer: 第22回日本ステロイドホルモン学会学術集会
  • Place of Presentation: 都道府県会館（東京都千代田区）
  • Year and Date: 2014-11-03
• [Remarks] 埼玉医科大学ゲノム医学研究センター遺伝子情報制御部門
  • URL: http://www.saitama-med.ac.jp/genome/Div02_GRST/index.html
• [Patent(Industrial Property Rights)] 二本鎖核酸分子、ＤＮＡ、ベクター、癌細胞増殖抑制剤、癌細胞移動抑制剤、及び医薬 (2015)
  • Inventor(s): 井上聡、池田和博、堀江公仁子
  • Industrial Property Rights Holder: 井上聡、池田和博、堀江公仁子
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-06-12
  • Overseas
• [Patent(Industrial Property Rights)] 二本鎖核酸分子、ＤＮＡ，ベクター、癌細胞増殖抑制剤、及び医薬 (2014)
  • Inventor(s): 井上聡、池田和博、堀江公仁子
  • Industrial Property Rights Holder: 井上聡、池田和博、堀江公仁子
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-122067
  • Filing Date: 2014-06-13