フルテキストURL K0005600_other1.pdf
著者 Takeda, Tatsuaki| Yamamoto, Hiromasa| Kanzaki, Hirotaka| Suzawa, Ken| Yoshioka, Takahiro| Tomida, Shuta| Cui, Xiaojiang| Murali, Ramachandran| Namba, Kei| Sato, Hiroki| Torigoe, Hidejiro| Watanabe, Mototsugu| Shien, Kazuhiko| Soh, Junichi| Asano, Hiroaki| Tsukuda, Kazunori| Kitamura, Yoshihisa| Miyoshi, Shinichiro| Sendo, Toshiaki| Toyooka, Shinichi|
抄録 BACKGROUND: Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in approximately 15-23% of breast cancers and these cancers are classified as HER2-positive breast cancer. Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer and has improved patient overall survival. However, acquired resistance to trastuzumab is still a critical issue in breast cancer treatment. We previously established a trastuzumab-resistant breast cancer cell line (named as BT-474-R) from a trastuzumab-sensitive HER2-amplified cell line BT-474. Lapatinib is also a molecular-targeted drug for HER2-positive breast cancer, which acquired the resistance to trastuzumab. Acquired resistance to lapatinib is also an issue to be conquered. METHODS: We established trastuzumab/lapatinib-dual resistant cell line (named as BT-474-RL2) by additionally treating BT-474-R with lapatinib. We analyzed the mechanisms of resistance to trastuzumab and lapatinib. Besides, we analyzed the effect of the detected resistance mechanism in HER2-positive breast cancer patients. RESULTS: Proto-oncogene tyrosine-protein kinase Yes1, which is one of the Src family members, was amplified, overexpressed and activated in BT-474-R and BT-474-RL2. Silencing of Yes1 by siRNA induced both BT-474-R and BT-474-RL2 to restore the sensitivity to trastuzumab and lapatinib. Pharmaceutical inhibition of Yes1 by the Src inhibitor dasatinib was also effective to restore the sensitivity to trastuzumab and lapatinib in the two resistant cell lines. Combination treatment with dasatinib and trastuzumab induced down-regulation of signaling molecules such as HER2 and Akt. Moreover, the combination treatments induced G1-phase cell-cycle arrest and apoptosis. Consistent with cell line data, high expression of Yes1 mRNA was correlated with worse prognosis in patients with HER2-positive breast cancer. CONCLUSION: Yes1 plays an important role in acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancer. Our data suggest that pharmacological inhibition of Yes1 may be an effective strategy to overcome resistance to trastuzumab and lapatinib.
備考 学位審査副論文
発行日 2017-02-03
出版物タイトル PLoS One
12巻
2号
出版者 Public Library of Science
開始ページ e0171356
ISSN 1932-6203
資料タイプ 学術雑誌論文
言語 English
OAI-PMH Set 岡山大学
著作権者 https://creativecommons.org/licenses/by-nc-nd/4.0/deed.ja
論文のバージョン publisher
PubMed ID 28158234
DOI 10.1371/journal.pone.0171356
Web of Sience KeyUT 000396161700064
関連URL isVersionOf https://doi.org/10.1371/journal.pone.0171356 isPartOf http://ousar.lib.okayama-u.ac.jp/55525