title: Amphiregulin confers trastuzumab resistance via AKT and ERK activation in HER2-positive breast cancer.
abstract: OBJECTIVE
  Human epidermal growth factor receptor 2 (HER2) heterodimerizes and shares common signaling pathways with epidermal growth factor receptor (EGFR). In this study, we investigated the clinical implication of amphiregulin, a ligand for EGFR, on trastuzumab therapy in HER2-positive breast cancer.
  
  
  METHODS
  Serum amphiregulin levels were quantified in 50 consecutive patients with HER2-positive metastatic breast cancer who received first-line trastuzumab plus taxane chemotherapy between October 2004 and July 2009. In addition, in vitro experiments were carried out to validate the results.
  
  
  RESULTS
  The median serum amphiregulin level was 1.0 ng/mL with a maximum level of 4.4 ng/mL. Patients with high serum amphiregulin levels (≥0.5 ng/mL) had significantly shorter progression-free survival (15.1 months vs. not reached; P = 0.018). Colony-forming assays demonstrated that the addition of amphiregulin resulted in increased proliferation of cells. In addition, the anti-proliferative effect of trastuzumab was decreased in the presence of amphiregulin. Western blot analysis showed that amphiregulin activated AKT and ERK pathways. In addition, in the presence of amphiregulin, sustained phosphorylation of AKT and ERK pathways was observed after trastuzumab treatment.
  
  
  CONCLUSIONS
  High serum amphiregulin levels were associated with early disease progression in these patients, possibly due to AKT and ERK signaling activation by amphiregulin.
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro-173-beon-gil, Seongnam, 463-707, Korea.
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Seoul International School, 15 Seongnam-daero-1518-beon-gil, Seongnam, 461-830, Korea.
authors.forename: Debora K
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea. mar6716@snu.ac.kr.
authors.forename: Ahrum
authors.initials: A
authors.lastname: Min
authors.affiliation: Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea. kyunghunlee@snu.ac.kr.|Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea. kyunghunlee@snu.ac.kr.
authors.forename: Kyung-Hun
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea.
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Nam
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro-173-beon-gil, Seongnam, 463-707, Korea.
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, SMG-SNU Boramae Medical Center, 20 Boramae-ro-5-gil, Seoul, 156-707, Korea.
authors.forename: Jin-Soo
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea.|Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea.|Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.affiliation: Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea.|Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Seoul, 110-744, Korea.
authors.forename: In Ae
authors.initials: IA
authors.lastname: Park
mesh_terms: D000328:Adult; D000368:Aged; D066258:Amphiregulin / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015996:Survival Rate; D000068878:Trastuzumab / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D066258:Amphiregulin; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: Amphiregulin; Breast cancer; HER2; Resistance; Trastuzumab