Diabetes mellitus is associated with breast cancer: systematic review, meta-analysis, and in silico reproduction

Aim. Breast cancer (BrCa) and diabetes mellitus (DM) are two major heath problems in women and the general population. This study explores the association between DM and breast cancer patients' survival outcomes, as well as the potential therapeutic merits of metformin. Methods. To explore the association between DM and BrCa, we performed systematic literature search in EMBASE (www.embase.com) and MEDLINE (www.ncbi.nlm.nih.gov/pubmed) from January 1960 to April 2014 and systematically identified clinical studies that assessed the association between BrCa mortality and DM. The NCBI Gene Expression Omnibus (GEO) database was analyzed to identify micro-RNA change in BrCa cells treated by metformin, a common drug for DM worldwide. Results. Twenty studies were selected for the meta-analysis, of which 16 reported all-cause mortality and 12 reported cancer specific death. During our inclusion period, the cohorts encompassed a total of 2,645,249 patients including more than 207,832 DM patients. Pre-existing DM was associated with a 37% increase of all-cause mortality risk for women with BrCa (HR=1.37; 95%CI: 1.34-1.41; P=0.02). DM was in general associated with a 17% increased risk for BrCa mortality in women (HR=1.17; 95%CI: 1.11-1.22; P<0.01). The GEO analysis revealed downregulation of a series of pro-tumorigenic microRNAs following metformin treatment, which was in part restored by DICER knockdown. Conclusion. Women with DM are at higher risk of BrCa-specific and all-cause mortality after initial breast cancer diagnosis. BrCa patients with DM could possibly benefit from metformin treatment via DICER mediation.