title: The effect of metformin on apoptosis in a breast cancer presurgical trial.
abstract: BACKGROUND
  Metformin has been associated with antitumour activity in breast cancer (BC) but its mechanism remains unclear. We determined whether metformin induced a modulation of apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) overall and by insulin resistance status in a presurgical trial.
  
  
  METHODS
  Apoptosis was analysed in core biopsies and in surgical samples from 100 non-diabetic BC patients participating in a randomised trial of metformin vs placebo given for 4 weeks before surgery.
  
  
  RESULTS
  Eighty-seven subjects (45 on metformin and 42 on placebo) were assessable for TUNEL measurement at both time points. TUNEL levels at surgery were higher than that at baseline core biopsy (P<0.0001), although no difference between arms was noted (metformin arm: median difference surgery-biopsy levels +4%, interquartile range (IQR): 2-12; placebo arm: +2%, IQR: 0-8, P=0.2). Ki67 labelling index and TUNEL levels were directly correlated both at baseline and surgery (Spearman's r=0.51, P<0.0001). In the 59 women without insulin resistance (HOMA index<2.8) ,there was a higher level of TUNEL at surgery on metformin vs placebo (median difference on metformin +4%, IQR: 2-14 vs +2%, IQR: 0-7 on placebo), whereas an opposite trend was found in the 28 women with insulin resistance (median difference on metformin +2%, IQR: 0-6, vs +5%, IQR: 0-15 on placebo, P-interaction=0.1).
  
  
  CONCLUSIONS
  Overall, we found no significant modulation of apoptosis by metformin, although there was a trend to a different effect according to insulin resistance status, with a pattern resembling Ki67 changes. Apoptosis was significantly higher in the surgical specimens compared with baseline biopsy and was directly correlated with Ki67. Our findings provide additional evidence for a dual effect of metformin on BC growth according to insulin resistance status.
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cazzaniga
authors.forename: A
authors.initials: A
authors.lastname: DeCensi
authors.forename: G
authors.initials: G
authors.lastname: Pruneri
authors.forename: M
authors.initials: M
authors.lastname: Puntoni
authors.forename: L
authors.initials: L
authors.lastname: Bottiglieri
authors.forename: C
authors.initials: C
authors.lastname: Varricchio
authors.forename: A
authors.initials: A
authors.lastname: Guerrieri-Gonzaga
authors.forename: O D
authors.initials: OD
authors.lastname: Gentilini
authors.forename: G
authors.initials: G
authors.lastname: Pagani
authors.forename: P
authors.initials: P
authors.lastname: Dell'Orto
authors.forename: M
authors.initials: M
authors.lastname: Lazzeroni
authors.forename: D
authors.initials: D
authors.lastname: Serrano
authors.forename: G
authors.initials: G
authors.lastname: Viale
authors.forename: B
authors.initials: B
authors.lastname: Bonanni
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D003131:Combined Modality Therapy; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D019394:Ki-67 Antigen / Q000032:analysis; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010919:Placebos; D057234:Preoperative Period
chemical_list: D007004:Hypoglycemic Agents; D019394:Ki-67 Antigen; D010919:Placebos; D008687:Metformin