title: Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer.
abstract: OBJECTIVE
  Vorinostat (suberoylanilide hydroxamic acid; SAHA) is a histone deacetylase inhibitor (HDACi) approved in the clinics for the treatment of T-cell lymphoma and with the potential to be effective also in breast cancer. We investigated the responsiveness to SAHA in human breast primary tumors and cancer cell lines.
  
  
  RESULTS
  We observed a differential response to drug treatment in both human breast primary tumors and cancer cell lines. Gene expression analysis of the breast cancer cell lines revealed that genes involved in cell adhesion and redox pathways, especially glutathione metabolism, were differentially expressed in the cell lines resistant to SAHA compared with the sensitive ones, indicating their possible association with drug resistance mechanisms. Notably, such an association was also observed in breast primary tumors. Indeed, addition of buthionine sulfoximine (BSO), a compound capable of depleting cellular glutathione, significantly enhanced the cytotoxicity of SAHA in both breast cancer cell lines and primary breast tumors.
  
  
  METHODS
  We identify and validate transcriptional differences in genes involved in redox pathways, which include potential predictive markers of sensitivity to SAHA.
  
  
  CONCLUSIONS
  In breast cancer, it could be relevant to evaluate the expression of antioxidant genes that may favor tumor resistance as a factor to consider for potential clinical application and treatment with epigenetic drugs (HDACis).
authors.affiliation: 1 Department of Biotechnology and Biosciences, University of Milano-Bicocca , Milan, Italy .|2 SYSBIO Centre of Systems Biology , Milan, Italy .
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Chiaradonna
authors.affiliation: 3 Department of Experimental Oncology, European Institute of Oncology , Milan, Italy .
authors.forename: Iros
authors.initials: I
authors.lastname: Barozzi
authors.affiliation: 3 Department of Experimental Oncology, European Institute of Oncology , Milan, Italy .
authors.forename: Claudia
authors.initials: C
authors.lastname: Miccolo
authors.affiliation: 3 Department of Experimental Oncology, European Institute of Oncology , Milan, Italy .
authors.forename: Gabriele
authors.initials: G
authors.lastname: Bucci
authors.affiliation: 1 Department of Biotechnology and Biosciences, University of Milano-Bicocca , Milan, Italy .|2 SYSBIO Centre of Systems Biology , Milan, Italy .
authors.forename: Roberta
authors.initials: R
authors.lastname: Palorini
authors.affiliation: 3 Department of Experimental Oncology, European Institute of Oncology , Milan, Italy .
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Fornasari
authors.affiliation: 3 Department of Experimental Oncology, European Institute of Oncology , Milan, Italy .
authors.forename: Oronza A
authors.initials: OA
authors.lastname: Botrugno
authors.affiliation: 4 Department of Pathology, European Institute of Oncology , Milan, Italy .
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pruneri
authors.affiliation: 4 Department of Pathology, European Institute of Oncology , Milan, Italy .
authors.forename: Michele
authors.initials: M
authors.lastname: Masullo
authors.affiliation: 3 Department of Experimental Oncology, European Institute of Oncology , Milan, Italy .
authors.forename: Alfonso
authors.initials: A
authors.lastname: Passafaro
authors.affiliation: 5 Department of Surgery, European Institute of Oncology , Milan, Italy .
authors.forename: Viviana E
authors.initials: VE
authors.lastname: Galimberti
authors.affiliation: 6 Oncology Research Unit, Pfizer Global Research and Development , La Jolla, California.
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Fantin
authors.affiliation: 7 Sanofi Oncology , Cambridge, Massachusetts.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Richon
authors.affiliation: 3 Department of Experimental Oncology, European Institute of Oncology , Milan, Italy .
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pece
authors.affiliation: 4 Department of Pathology, European Institute of Oncology , Milan, Italy .
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.affiliation: 3 Department of Experimental Oncology, European Institute of Oncology , Milan, Italy .
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.affiliation: 8 Institute for Applied Cancer, The University of Texas MD Anderson Cancer Center Science , Houston, Texas.
authors.forename: Giulio
authors.initials: G
authors.lastname: Draetta
authors.affiliation: 3 Department of Experimental Oncology, European Institute of Oncology , Milan, Italy .
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.affiliation: 3 Department of Experimental Oncology, European Institute of Oncology , Milan, Italy .|9 Department of Biosciences, University of Milan , Milan, Italy .
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.affiliation: 3 Department of Experimental Oncology, European Institute of Oncology , Milan, Italy .
authors.forename: Susanna
authors.initials: S
authors.lastname: Chiocca
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D010084:Oxidation-Reduction / Q000187:drug effects; D061251:Primary Cell Culture; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019328:Buthionine Sulfoximine; D000077337:Vorinostat