title: Heregulin-expressing HER2-positive breast and gastric cancer exhibited heterogeneous susceptibility to the anti-HER2 agents lapatinib, trastuzumab and T-DM1.
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.
  
  
  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.
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Yoshikane
authors: Y
authors: Nonagase
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Kimio
authors: K
authors: Yonesaka
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Hisato
authors: H
authors: Kawakami
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Satomi
authors: S
authors: Watanabe
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Koji
authors: K
authors: Haratani
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Takayuki
authors: T
authors: Takahama
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Naoki
authors: N
authors: Takegawa
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Hiroto
authors: H
authors: Ueda
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Junko
authors: J
authors: Tanizaki
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Hidetoshi
authors: H
authors: Hayashi
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Takeshi
authors: T
authors: Yoshida
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Masayuki
authors: M
authors: Takeda
authors: Clinical Research Center, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Yasutaka
authors: Y
authors: Chiba
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Takao
authors: T
authors: Tamura
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Kazuhiko
authors: K
authors: Nakagawa
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.
authors: Junji
authors: J
authors: Tsurutani
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D000077341:Lapatinib; D008297:Male; D008453:Maytansine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008875:Middle Aged; D020890:Neuregulin-1 / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy*; D000077022:Survivin; D000068878:Trastuzumab / Q000627:therapeutic use*
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D051034:Inhibitor of Apoptosis Proteins; D000077341:Lapatinib; D008453:Maytansine; D020890:Neuregulin-1; D051058:Oncogene Protein v-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000077022:Survivin; D000068878:Trastuzumab; C107489:BIRC5 protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: HER2; T-DM1; breast cancer; heregulin; resistance