title: Role of p53 codon 72 arginine allele in cell survival in vitro and in the clinical outcome of patients with advanced breast cancer.
abstract: BACKGROUND
  The p53 codon 72 polymorphism, which results in either an arginine or proline residue, plays a different role in vitro and in vivo in cell survival and drug resistance. We verified, in vitro, the impact of the arginine allele on cell survival under normoxia and hypoxia, and investigated in vivo the role of p53 codon 72 arginine homozygosity in the clinical outcome of advanced breast cancer patients.
  
  
  METHODS
  Tumors at advanced stages grow in vivo in a hypoxic environment, and we mimicked such conditions in vitro using p53 null breast cancer cells transfected with either the arginine or proline allele. We also analyzed in vivo the p53 codon 72 genotype status of advanced breast cancer patients.
  
  
  RESULTS
  In vitro transfection of the arginine allele induced higher cell death under normoxia, whereas cell death was greater in proline-transfected cells under hypoxia. The arginine allele upregulated BCRP-I, a hypoxia response gene, which increases drug resistance. Metastatic breast cancer patients homozygous for arginine had a significantly shorter time to progression and overall survival than those with heterozygous arginine/proline tumors.
  
  
  CONCLUSIONS
  We provide a molecular explanation for the association of the arginine allele with tumor aggressiveness and treatment resistance in advanced breast cancer.
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Vannini
authors.forename: W
authors.initials: W
authors.lastname: Zoli
authors.forename: A
authors.initials: A
authors.lastname: Tesei
authors.forename: M
authors.initials: M
authors.lastname: Rosetti
authors.forename: P
authors.initials: P
authors.lastname: Sansone
authors.forename: G
authors.initials: G
authors.lastname: Storci
authors.forename: A
authors.initials: A
authors.lastname: Passardi
authors.forename: I
authors.initials: I
authors.lastname: Massa
authors.forename: M
authors.initials: M
authors.lastname: Ricci
authors.forename: D
authors.initials: D
authors.lastname: Gusolfino
authors.forename: F
authors.initials: F
authors.lastname: Fabbri
authors.forename: P
authors.initials: P
authors.lastname: Ulivi
authors.forename: G
authors.initials: G
authors.lastname: Brigliadori
authors.forename: D
authors.initials: D
authors.lastname: Amadori
authors.forename: M
authors.initials: M
authors.lastname: Bonafe
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000368:Aged; D000483:Alleles; D001120:Arginine / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D003062:Codon / Q000235:genetics*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011392:Proline / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D003062:Codon; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D001120:Arginine; D011392:Proline