Primed for death: prognostic role of BH3--only proteins in breast cancer therapy: a systematic and meta-analysis review

Abstract

Breast cancer (BC) is the primary cause of cancer-related deaths among women. BH3 only proteins expression profile in BC has been linked to chemotherapy and treatment outcomes. Clinical biomarkers provide insights into disease progression. Therefore, we systematically investigated the prognostic significance of proapoptotic Bcl-2 Homology Domain 3 (BH3) only proteins in Disease-Free Survival (DFS) and Overall Survival (OS) among BC patients. We explored four databases, screening titles, abstracts, and full articles based on predefined criteria. The quality of cohort studies and randomized clinical trials were assessed. Data of BH3-only gene and proteins’ expression were extracted and meta-analysis using random effects model was performed. Of the 3541 studies identified, nine studies met inclusion criteria. The meta-analysis revealed that the BH3-only protein-positive group had a higher chance of 5-year DFS risk ratio (RR = 1.17, 95% CI [0.94, 1.46], P = 0.16) and significantly improved 10-year DFS (RR = 1.32, 95% CI [1.15, 1.50], P = 0.0001). Subgroup analysis indicated that BCL-2 antagonist of cell death (BAD) positive expression significantly correlated with improved 5-year DFS (RR = 1.34, 95% CI [1.06, 1.70], P = 0.02), while p53 upregulated modulator of apoptosis (PUMA) positive expression showed a limited association with improved 5-year OS (RR = 1.13, 95% CI [1.03, 1.25], P = 0.01). Conversely, BCL-2 interacting killer (BIK) positive expression was significantly associated with worsened 5-year DFS (RR = 0.84, 95% CI [0.73, 0.97], P = 0.02) but not OS. While BAD and PUMA positive expression correlated significantly with patients’ improved OS and/or DFS, BIK and BCL-2 interacting mediator of cell death (BIM) high expression were correlated with poor survival outcome. This data suggests, despite being from the same family, these BH3-only proteins induce different tumor survival signaling pathways, that could play role in predicting/leading to a good or poor OS as well as DFS outcomes in BC patients after treatment. Limited data suggests further studies are needed to confirm BAD and PUMA BH3-only protein positive expression as independent prognostic variables for 5-year DFS and OS, respectively, in BC patients.