Clinical significance and molecular mechanism elucidation of E-cadherin expression in triple-negative breast cancer

2016 Fiscal Year Annual Research Report

• Project/Area Number: 26461957
• Research Institution: Osaka City University
• Principal Investigator: 柏木 伸一郎 大阪市立大学, 大学院医学研究科, 講師 (80637017)
• Co-Investigator(Kenkyū-buntansha): 川尻 成美 大阪市立大学, 大学院医学研究科, 登録医 (40597283) [Withdrawn] ; 大平 雅一 大阪市立大学, 大学院医学研究科, 教授 (90203926) ; 高島 勉 大阪市立大学, 大学院医学研究科, 講師 (80336776)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: トリプルネガティブ乳癌 / 個別化治療 / 上皮間葉転換 / E-cadherin

Outline of Annual Research Achievements

近年，乳癌においてはestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) の発現状況などからホルモン療法や分子標的療法などが選択されている．ER, PR, HER2が陰性であるトリプルネガティブ乳癌 (triple-negative breast cancer, TNBC) では明らかなターゲットがなく治療法はいまだ確立されていない．申請者はこれまでにTNBCの化学療法感受性を予測し得るバイオマーカーとしてE-cadherinが有用であることを明らかにしてきた．本研究はE-cadherinの発現の有無によりTNBCを細分類し，メチル化解析などの基礎的研究をすすめ，その分子機構の解明を図り，治療抵抗性と考えられるE-cadherin陰性症例をターゲットとした治療の探索と検証を目的とするものである．
分子生物学的アプローチにより，EMTを介したTNBCの悪性形質獲得の検証をすすめた．EMTの制御に関わるmicro-RNA (miR) 200bをLentiviral miRNA Expression Vectorを用いてTNBC細胞株にtransfectionさせ，安定細胞株であるmicro-RNA 200b強制発現TNBC細胞株 (miR200b MDA-MB-231) を樹立した．また，Lipofectamine® 3000 Reagentを用いてE-cadherin-GFP Plasmid VectorにてE-cadherin強制発現TNBC細胞株 (E-cadherin MDA-MB-231) を樹立し，これらの細胞株をEMT抑制モデルとして親株との比較検証をすすめたところ，EMT抑制モデルはluminalタイプに類似した細胞特性を有していた．さらに同様の手法を用いて，pEGFP-C1-AR Plasmid Vectorを導入したAR強制発現TNBC細胞株 (AR MDA-MB-231) を作成したところ，AR MDA-MB-231は内分泌療法やホルモン受容体陽性乳癌に対する新たな分子標的薬として期待されているpalbociclib (CDK4/6阻害剤) に感受性を有しており，これらのTNBCサブタイプに対する新たな治療戦略の可能性を明らかにした (AACR 2017)．

Research Products

• [Journal Article] Expression and clinical significance of androgen receptor in triple-negative breast cancer. (2017)
  • Author(s): Asano Y, Kashiwagi S, Goto W, Takada K, Tanaka S, Morisaki T, Takashima T, Noda S, Onoda N, Ohsawa M, Hirakawa K, Ohira M.
  • Journal Title: Cancers Volume: 9 Pages: 4
  • DOI: 10.3390/cancers9010004
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A case of multiple metastatic malignant phyllodes tumor of the breast with tonsillar metastasis. (2017)
  • Author(s): Sera T, Kashiwagi S, Takashima T, Asano Y, Goto W, Iimori N, Noda S, Onoda N, Ohsawa M, Hirakawa K, Ohira M.
  • Journal Title: BMC Res Notes Volume: 10 Pages: 55
  • DOI: 10.1186/s13104-017-2375-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Use of tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer. (2017)
  • Author(s): Kashiwagi S, Asano Y, Goto W, Takada K, Takahashi K, Noda S, Takashima T, Onoda N, Tomita S, Ohsawa M, Hirakawa K, Ohira M.
  • Journal Title: PLoS ONE Volume: 12 Pages: e0170634
  • DOI: 10.1371/journal.pone.0170634
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tumour-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to neoadjuvant chemotherapy of aggressive breast cancer. (2016)
  • Author(s): Asano Y, Kashiwagi S, Goto W, Kurata K, Noda S, Takashima T, Onoda N, Tanaka S, Ohsawa M, Hirakawa K.
  • Journal Title: Br J Surg Volume: 103 Pages: 845-854
  • DOI: 10.1002/bjs.10127
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical verification of sensitivity to preoperative chemotherapy in cases of androgen receptor-expressing positive breast cancer. (2016)
  • Author(s): Asano Y, Kashiwagi S, Onoda N, Kurata K, Morisaki T, Noda S, Takashima T, Ohsawa M, Kitagawa S, Hirakawa K.
  • Journal Title: Br J Cancer Volume: 12 Pages: 14-20
  • DOI: 10.1038/bjc.2015.434
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Predictive Value of Neutrophil/Lymphocyte Ratio for Efficacy of Preoperative Chemotherapy in Triple-Negative Breast Cancer. (2016)
  • Author(s): Asano Y, Kashiwagi S, Onoda N, Noda S, Kawajiri H, Takashima T, Ohsawa M, Kitagawa S, Hirakawa K.
  • Journal Title: Ann Surg Oncol Volume: 23 Pages: 1104-1110
  • DOI: 10.1245/s10434-015-4934-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Platelet lymphocyte ratio as a useful predictor of the therapeutic effect of neoadjuvant chemotherapy in breast cancer. (2016)
  • Author(s): Asano Y, Kashiwagi S, Onoda N, Noda S, Kawajiri H, Takashima T, Ohsawa M, Kitagawa S, Hirakawa K.
  • Journal Title: PLoS ONE Volume: 11 Pages: e0153459
  • DOI: 10.1371/journal.pone.0153459
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Predicting therapeutic effect by on tumor-infiltrating lymphocytes (TILs) in endocrine therapy for stage IV breast cancer (2016)
  • Author(s): Shinichiro Kashiwagi, Yuka Asano, Wataru Goto, Koji Takada, Tsutomu Takashima, Tamami Morisaki, Satoru Noda, Naoyoshi Onoda, Masahiko Ohsawa, Kosei Hirakawa, Masaichi Ohira
  • Organizer: San Antonio Breast Cancer Symposium (SABCS)
  • Place of Presentation: San Antonio, Texas, USA
  • Year and Date: 2016-12-06 – 2016-12-10
  • Int'l Joint Research
• [Presentation] Prediction of The Treatment Response to Docetaxel, Trastuzumab and Pertuzumab Combination Regimen Chemotherapy in Breast Cancer using TILs (2016)
  • Author(s): Shinichiro Kashiwagi, Tsutomu Takashima, Yuka Asano, Wataru Goto, Koji Takada, Tamami Morisaki, Satoru Noda, Naoyoshi Onoda, Kosei Hirakawa, Masaichi Ohira
  • Organizer: 4th Federation of Asian Clinical Oncology (FACO)
  • Place of Presentation: Amoi, China
  • Year and Date: 2016-09-22
  • Int'l Joint Research
• [Presentation] Prediction of the treatment response to eribulin chemotherapy in breast cancer using tumor-infiltrating lymphocytes (TILs) (2016)
  • Author(s): Shinichiro Kashiwagi, Yuka Asano, Wataru Goto, Kento Kurata, Tamami Morisaki, Satoru Noda, Tsutomu Takashima, Naoyoshi Onoda, Sayaka Tanaka, Masahiko Ohsawa, Masaichi Ohira, Kosei Hirakawa
  • Organizer: American Association for Cancer Research (AACR)
  • Place of Presentation: New Orleans, Louisiana, USA
  • Year and Date: 2016-04-16 – 2016-04-20
  • Int'l Joint Research
• [Remarks] 大阪市立大学大学院医学研究科腫瘍外科学講座
  • URL: http://www.med.osaka-cu.ac.jp/departments/zouki-g-surgical-oncology.shtml