title: Regulation of hepatocyte growth factor activator inhibitor 2 by hypoxia in breast cancer.
abstract: OBJECTIVE
  To examine the in vitro regulation of hepatocyte growth factor activator inhibitor type 2 (HAI-2) in breast cancer cells and the in vivo predictive role for the efficacy of chemoendocrine primary therapy in patients with breast cancer.
  
  
  METHODS
  HAI-2 regulation was studied in a panel of breast cancer cell lines comparing normoxia to hypoxia. The effect of HIF-1alpha RNAi on HAI-2 expression was evaluated in these cells. HAI-2 was examined in breast cancer using in situ hybridization and immunohistochemistry. The HAI-2 predictive role was assessed in T(2-4) N(0-1) breast cancers (n = 177) enrolled in a neoadjuvant randomized trial comparing epirubicin versus epirubicin + tamoxifen.
  
  
  RESULTS
  HAI-2 mRNA and protein were regulated by hypoxia in the c-erbB2-positive cell lines, SKBR3 and BT474, and controlled by HIF-1alpha in these cells. Immunohistochemistry confirmed this profile with high expression of HAI-2 in c-erbB2-positive breast cancer. HAI-2 was correlated with T status (P < 0.004), node involvement (P = 0.01), and c-erbB2 expression (P = 0.05). HAI-2 also correlated with hypoxia markers such as carbonic anhydrase IX expression (P = 0.01) and HIF-1alpha. Additionally, high levels of HAI-2 were a significant predictor for poor clinical complete response to preoperative epirubicin in univariate (P = 0.01) and multivariate analyses (P = 0.016). No correlation with disease-free survival and survival was observed.
  
  
  CONCLUSIONS
  HAI-2 expression in breast cancer correlated with tumor aggressiveness in vivo. It is a HIF target in c-erbB2-positive cells and it is an independent negative predictive factor of efficacy of anthracycline therapy. The interaction of HAI-2 with the hepatocyte growth factor activation pathway may be a useful site for therapeutic intervention.
authors.affiliation: Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Daniele
authors.initials: D
authors.lastname: Generali
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
authors.forename: Alfredo
authors.initials: A
authors.lastname: Berruti
authors.forename: John W
authors.initials: JW
authors.lastname: Moore
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Brizzi
authors.forename: Nilay
authors.initials: N
authors.lastname: Patel
authors.forename: Giovanni
authors.initials: G
authors.lastname: Allevi
authors.forename: Simone
authors.initials: S
authors.lastname: Bonardi
authors.forename: Sergio
authors.initials: S
authors.lastname: Aguggini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bersiga
authors.forename: Leticia
authors.initials: L
authors.lastname: Campo
authors.forename: Luigi
authors.initials: L
authors.lastname: Dogliotti
authors.forename: Alberto
authors.initials: A
authors.lastname: Bottini
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000951:Antigens, Neoplasm / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008562:Membrane Glycoproteins / Q000378:metabolism*; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D000951:Antigens, Neoplasm; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D008562:Membrane Glycoproteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C109148:SPINT2 protein, human; C089226:CA9 protein, human