title: Neuregulin expression modulates clinical response to trastuzumab in patients with metastatic breast cancer.
abstract: OBJECTIVE
  Human epidermal growth factor receptor 2 (HER-2) overexpression has been associated with the genesis and progression of a subset of breast cancers. The function of HER-2 may be upregulated by overexpression or by the availability of neuregulins (NRGs), a group of transmembrane growth factors. Transmembrane NRGs strongly activated HER-2 and cell proliferation in breast cancer cells that did not overexpress HER-2, and treatment with trastuzumab prevented the proliferative action of transmembrane NRG. This raised the relevant clinical question of whether patients considered as HER-2 negative, but expressing transmembrane NRG, may benefit from treatment with trastuzumab.
  
  
  METHODS
  MCF7 cells expressing transmembrane NRG (MCF7-NRG2c) were injected into mice, and their sensitivity to trastuzumab was assessed. A retrospective study of 124 patients with early-stage or metastatic breast cancer was conducted. Expression of transmembrane NRG was evaluated by immunohistochemistry. In 11 patients, Western blot for NRGs was also carried out. Statistics were performed to analyze possible correlations between NRG expression and response to trastuzumab-based therapies, event-free survival, and overall survival (OS).
  
  
  RESULTS
  Trastuzumab inhibited tumor growth in mice injected with MCF7-NRG2c cells. Transmembrane NRG was frequently expressed in breast cancer patients. Overexpression of transmembrane NRG significantly correlated with a longer event-free survival and OS in patients with low or normal HER-2 expression who were treated with trastuzumab-based therapies but not in patients with HER-2 overexpression.
  
  
  CONCLUSIONS
  We suggest that the spectrum of patients who may benefit from trastuzumab-based therapies may be widened to include patients with metastatic breast cancer without HER-2 amplification but who express transmembrane NRGs.
authors.affiliation: Centro de Investigación del Cáncer-Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, and Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: de Alava
authors.forename: Alberto
authors.initials: A
authors.lastname: Ocaña
authors.forename: Mar
authors.initials: M
authors.lastname: Abad
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Montero
authors.forename: Azucena
authors.initials: A
authors.lastname: Esparís-Ogando
authors.forename: César A
authors.initials: CA
authors.lastname: Rodríguez
authors.forename: Ana P
authors.initials: AP
authors.lastname: Otero
authors.forename: Teresa
authors.initials: T
authors.lastname: Hernández
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Cruz
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D020880:Neuregulins / Q000096:biosynthesis*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012189:Retrospective Studies; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D020880:Neuregulins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab