トリプルネガティブ乳癌におけるEカドヘリン発現の分子機構の解明および臨床的意義

2014 Fiscal Year Research-status Report

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

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．

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

細胞株や臨床検体を用いた研究ともに，結果が集積されてきている．断片的な結果も多いが，総量としては十分な知見があり，想定した結果が期待される．
TNBCの細分類はE-cadherinの発現だけでなく，アンドロゲン受容体 (AR) の発現の臨床的検証をすすめ，新たな個別化治療 (AR陽性TNBCに対する内分泌療法) の可能性を明らかにした．さらに高免疫活性のTNBCを明らかにすべく腫瘍内リンパ球浸潤 (TILs) や免疫関連遺伝子 (PD-1, PDL-1など) の探索もすすめている．初年度であり研究結果については，系統だった考察までには至らないが，全体としては今後の研究総括に向けて順調な進捗と思われる．

Strategy for Future Research Activity

27年度は，今年度の研究結果を更に具体的な研究をすすめていく．現時点では遺伝子プロファイルによるTNBC細分類を簡易な免疫組織染色やFACSなどの簡易な代替手法が可能かどうかの検索をすすめていくのと同時に，それぞれの細分類の分子機構を明らかにしてく．

Causes of Carryover

本年度は抗体や実験器具などの消耗品に費用を使用したため、実験に費用がかからなかた。

Expenditure Plan for Carryover Budget

羅的解析など費用が高額となる研究を次年度に予定している。

Research Products

• [Journal Article] Ambulatory sentinel lymph node biopsy preceding neoadjuvant therapy in patients with operable breast cancer: a preliminary study. (2015)
  • Author(s): Kashiwagi S, Onoda N, Asano Y, Kurata K, Noda S, Kawajiri H, Takashima T, Ohsawa M, Kitagawa S, Hirakawa K.
  • Journal Title: World J Surg Oncol Volume: 13 Pages: 53
  • DOI: 10.1186/s12957-015-0471-3.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Nonfunctional adrenocortical carcinoma initially presenting as retroperitoneal haemorrhage. (2015)
  • Author(s): Kashiwagi S, Amano R, Onoda N, Noda S, Hirata K, Asano Y, Kurata K, Miura K, Yamazoe S, Kimura K, Ohsawa M, Kitagawa S, Hirakawa K.
  • Journal Title: BMC Surgery Volume: 15 Pages: 46
  • DOI: doi:10.1186/s12893-015-0031-3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer. (2015)
  • Author(s): Kawajiri H, Takashima T, Kashiwagi S, Noda S, Onoda N, Hirakawa K.
  • Journal Title: Expert Rev Anticancer Ther. Volume: 15 Pages: 17-26
  • DOI: 10.1586/14737140.2015.992418
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] T-stage and positive sentinel nodes ratio are the useful factors to predict non-sentinel node metastasis in breast cancer patients with macro-metastasis in the sentinel node. (2015)
  • Author(s): Noda S, Onoda N, Asano Y, Kurata K, Kashiwagi S, Kawajiri H, Takashima T, Hirakawa K.
  • Journal Title: Int J Surg Volume: 14 Pages: 56-60
  • DOI: 10.1016/j.ijsu.2015.01.006.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A rare recurrence of bilateral breast cancer in the esophagus coincidentally associated with primary gastric cancer: a case report. (2014)
  • Author(s): Kashiwagi S, Onoda N, Asano Y, Noda S, Kawajiri H, Takashima T, Ishikawa T, Hirakawa K.
  • Journal Title: J Med Case Rep Volume: 8 Pages: 58
  • DOI: 10.1186/1752-1947-8-58.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 24.Strategy of operative treatment of hyperparathyroidism using US scan and 99mTc-MIBI SPECT/CT. (2014)
  • Author(s): Noda S, Onoda N, Kashiwagi S, Kawajiri H, Takashima T, Ishikawa T, Yoshida A, Higashiyama S, Kawabe J, Imanishi Y, Tahara H, Inaba M, Osawa M, Hirakawa K.
  • Journal Title: Endcrine J Volume: 61 Pages: 225-230
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 23.Establishment, characterization and comparison of seven authentic anaplastic thyroid cancer cell lines retaining clinical features of the original tumors. (2014)
  • Author(s): Onoda N, Nakamura M, Aomatsu N, Noda S, Kashiwagi S, Hirakawa K.
  • Journal Title: World J Surg Volume: 38 Pages: 688-695
  • DOI: 10.1007/s00268-013-2409-7.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 21.Prognostic significance of pathological complete response following neoadjuvant chemotherapy for operable breast cancer. (2014)
  • Author(s): Kawajiri H, Takashima T, Aomatsu N, Kashiwagi S, Noda S, Onoda N, Ishikawa T, Hirakawa K.
  • Journal Title: Oncology Letters Volume: 7 Pages: 663-668
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 20.E-cadherin expression and cell proliferation in the primary tumor and metastatic lymph nodes of papillary thyroid mirocarcinoma. (2014)
  • Author(s): Nakamura M, Onoda N, Noda S, Kashiwagi S, Aomatsu N, Kurata K, Kawajiri H, Takashima T, Ishikawa T, Hirakawa K.
  • Journal Title: Mol Clin Oncol Volume: 2 Pages: 226-232
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 19.Carbonic anhydrase 9 is associated with chemosensitivity and prognosis in breast cancer patients treated with taxane and anthracycline. (2014)
  • Author(s): Aomatsu N, Yashiro M, Kashiwagi S, Kawajiri H, Takashima T, Ohsawa M, Wakasa K, Hirakawa K.
  • Journal Title: BMC Cancer Volume: 14 Pages: 400
  • DOI: 10.1186/1471-2407-14-400.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Kashiwagi S, Asano Y, Morisaki T, Noda S, Kawajiri H, Takashima T, Onoda N, Hirakawa K. (2015)
  • Author(s): Epithelial-mesenchymal transition and tumor vascular remodeling in eribulin chemotherapy for breast cancer
  • Organizer: American Association for Cancer Research 2015
  • Place of Presentation: Philadelphia (USA)
  • Year and Date: 2015-04-18 – 2015-04-22
• [Presentation] Predictive Value of Neutrophil-Lymphocyte Ratio for the Efficacy of Preoperative Chemotherapy in Triple-negative Breast Cancer (2015)
  • Author(s): Asano Y, Kashiwagi S, Morisaki T, Noda S, Kawajiri H, Takashima T, Onoda N, Hirakawa K.
  • Organizer: American Association for Cancer Research 2015
  • Place of Presentation: Philadelphia (USA)
  • Year and Date: 2015-04-18 – 2015-04-22
• [Presentation] 15.TLE3 is a useful marker for predicting the therapeutic effect of eribulin chemotherapy for triple-negative breast cance. (2014)
  • Author(s): Kashiwagi S, Asano Y, Kurata K, Morisaki T, Noda S, Kawajiri H, Takashima T, Onoda N, Maeda K, Hirakawa K.
  • Organizer: 39th European Society for Medical Oncology
  • Place of Presentation: Madrid (Spain)
  • Year and Date: 2014-09-26 – 2014-09-30
• [Presentation] 16.Expression and clinical significance of androgen receptor in triple-negative breast cancer. (2014)
  • Author(s): Asano Y, Kashiwagi S, Kurata K, Morisaki T, Noda S, Kawajiri H, Takashima T, Onoda N, Maeda K, Hirakawa K.
  • Organizer: 39th European Society for Medical Oncology
  • Place of Presentation: Madrid (Spain)
  • Year and Date: 2014-09-26 – 2014-09-30