title: Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers.
abstract: BACKGROUND
  Molecular segmentation of breast cancer allows identification of small groups of patients who present high sensitivity to targeted agents. A patient, with chemo- and trastuzumab-resistant HER2-overexpressing breast cancer, who presented concomitant acute promyelocytic leukemia, showed a response in her breast lesions to retinoic acid, arsenic, and aracytin. We therefore investigated whether RARA gene amplification could be associated with sensitivity to retinoic acid derivatives in breast cancers.
  
  
  METHODS
  Array comparative genomic hybridization and gene expression arrays were used to characterize RARA amplifications and expression in 103 breast cancer samples. In vitro activity of ATRA was characterized in T47D, SKBR3, and BT474 cell lines.
  
  
  RESULTS
  Retinoic acid receptor alpha was gained or amplified in 27% of HER2-positive and 13% of HER2-negative breast cancer samples. Retinoic acid receptor alpha can be coamplified with HER2. Retinoic acid receptor alpha copy number changes could be correlated with messenger RNA expression. All-trans-retinoic acid reduced cell viability of RARA-amplified, but not RARA-normal, cell lines through apoptosis. Gene expression arrays showed that ATRA-induced apoptosis in RARA-amplified cell lines was related to an increase in CASP1 and IRF1.
  
  
  CONCLUSIONS
  The results of this study suggest that breast cancers exhibiting RARA amplifications could be sensitive to retinoic acid. A phase II trial will evaluate this hypothesis in the clinical setting.
authors.affiliation: INSERM U981 "Identification of molecular predictors and new targets for cancer treatment", Gustave Roussy Cancer Institute, Villejuif, France.
authors.forename: Samar
authors.initials: S
authors.lastname: Alsafadi
authors.forename: Caroline
authors.initials: C
authors.lastname: Even
authors.forename: Coralie
authors.initials: C
authors.lastname: Falet
authors.forename: Aicha
authors.initials: A
authors.lastname: Goubar
authors.forename: Frédéric
authors.initials: F
authors.lastname: Commo
authors.forename: Véronique
authors.initials: V
authors.lastname: Scott
authors.forename: Virginie
authors.initials: V
authors.lastname: Quidville
authors.forename: Laurence
authors.initials: L
authors.lastname: Albiges
authors.forename: Maria-Vittoria
authors.initials: MV
authors.lastname: Dieci
authors.forename: Justine
authors.initials: J
authors.lastname: Guegan
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lazar
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Ahomadegbe
authors.forename: Suzette
authors.initials: S
authors.lastname: Delaloge
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D008875:Middle Aged; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D000068878:Trastuzumab; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D000068878:Trastuzumab
keywords: All-trans-retinoic acid; Coamplification; HER2; IRF1; RARA