The effect of metformin on apoptosis in a breast cancer presurgical trial.
Author(s): Cazzaniga M(1), DeCensi A, Pruneri G, Puntoni M, Bottiglieri L, Varricchio C,
Guerrieri-Gonzaga A, Gentilini OD, Pagani G, Dell'Orto P, Lazzeroni M, Serrano D,
Viale G, Bonanni B.
Affiliation(s): Author information:
(1)Division of Cancer Prevention and Genetics, European Institute of Oncology, Via
Ripamonti 435, 20141 Milan, Italy.
Publication date & source: 2013, Br J Cancer. , 109(11):2792-7
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).
CONCLUSION: 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.
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