Heregulin-expressing HER2-positive breast and gastric cancer exhibited heterogeneous susceptibility to the anti-HER2 agents lapatinib, trastuzumab and T-DM1
| Autor: | Masayuki Takeda, Junko Tanizaki, Hidetoshi Hayashi, Naoki Takegawa, Koji Haratani, Yoshikane Nonagase, Takeshi Yoshida, Satomi Watanabe, Takayuki Takahama, Kimio Yonesaka, Hiroto Ueda, Takao Tamura, Junji Tsurutani, Hisato Kawakami, Kazuhiko Nakagawa, Yasutaka Chiba |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology Male Receptor ErbB-3 Receptor ErbB-2 Survivin T-DM1 Apoptosis Ado-Trastuzumab Emtansine Inhibitor of Apoptosis Proteins chemistry.chemical_compound 0302 clinical medicine heregulin Trastuzumab Recombinant Heregulin skin and connective tissue diseases Middle Aged Oncogene Protein v-akt Paclitaxel 030220 oncology & carcinogenesis Neuregulin Female medicine.drug Signal Transduction Research Paper medicine.medical_specialty animal structures Neuregulin-1 Breast Neoplasms Lapatinib resistance 03 medical and health sciences Breast cancer breast cancer Stomach Neoplasms Internal medicine Cell Line Tumor HER2 medicine Humans Maytansine neoplasms Aged Cell Proliferation business.industry Cancer medicine.disease 030104 developmental biology chemistry Trastuzumab emtansine Drug Resistance Neoplasm Quinazolines business |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Yoshikane Nonagase 1 , Kimio Yonesaka 1 , Hisato Kawakami 1 , Satomi Watanabe 1 , Koji Haratani 1 , Takayuki Takahama 1 , Naoki Takegawa 1 , Hiroto Ueda 1 , Junko Tanizaki 1 , Hidetoshi Hayashi 1 , Takeshi Yoshida 1 , Masayuki Takeda 1 , Yasutaka Chiba 2 , Takao Tamura 1 , Kazuhiko Nakagawa 1 , Junji Tsurutani 1 1 Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan 2 Clinical Research Center, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan Correspondence to: Junji Tsurutani, email: tsurutani_j@dotd.med.kindai.ac.jp Keywords: HER2, T-DM1, resistance, heregulin, breast cancer Received: March 28, 2016 Accepted: October 01, 2016 Published: October 19, 2016 ABSTRACT Background: Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer. Results: Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel. The heregulin mRNA level of one of 10 patients was up-regulated after the acquisition of resistance to trastuzumab-based therapy. Materials and Methods: SK-BR-3, NCI-N87, BT-474, MDA-MB-453, HCC1954, SNU-216 and 4-1ST cells were pharmacologically treated with recombinant heregulin or transfected with the heregulin gene. We also assessed the expression of heregulin mRNA in HER2-positive breast or gastric cancer samples before and after trastuzumab-based therapy using a RT-PCR-based method. Conclusions: mRNA up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo. |
| Databáze: | OpenAIRE |
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