TY - JOUR
T1 - The effect of metformin on apoptosis in a breast cancer presurgical trial
AU - Cazzaniga, M.
AU - DeCensi, A.
AU - Pruneri, G.
AU - Puntoni, M.
AU - Bottiglieri, L.
AU - Varricchio, C.
AU - Guerrieri-Gonzaga, A.
AU - Gentilini, O. D.
AU - Pagani, G.
AU - Dell'Orto, P.
AU - Lazzeroni, M.
AU - Serrano, D.
AU - Viale, G.
AU - Bonanni, B.
PY - 2013/11/26
Y1 - 2013/11/26
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Breast cancer
KW - Insulin resistance
KW - Ki67
KW - Metformin
KW - Neoadjuvant study
UR - http://www.scopus.com/inward/record.url?scp=84888870836&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84888870836&partnerID=8YFLogxK
U2 - 10.1038/bjc.2013.657
DO - 10.1038/bjc.2013.657
M3 - Article
C2 - 24157825
AN - SCOPUS:84888870836
VL - 109
SP - 2792
EP - 2797
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 11
ER -