title: Caspase-3 and caspase-8 expression in breast cancer: caspase-3 is associated with survival.
abstract: Impaired apoptosis is one of the hallmarks of cancer. Caspase-3 and -8 are key regulators of the apoptotic response and have been shown to interact with the calpain family, a group of cysteine proteases, during tumorigenesis. The current study sought to investigate the prognostic potential of caspase-3 and -8 in breast cancer, as well as the prognostic value of combinatorial caspase and calpain expression. A large cohort (n = 1902) of early stage invasive breast cancer patients was used to explore the expression of caspase-3 and -8. Protein expression was examined using standard immunohistochemistry on tissue microarrays. High caspase-3 expression, but not caspase-8, is significantly associated with adverse breast cancer-specific survival (P = 0.008 and P = 0.056, respectively). Multivariate analysis showed that caspase-3 remained an independent factor when confounding factors were included (hazard ratio (HR) 1.347, 95% confidence interval (CI) 1.086-1.670; P = 0.007). The analyses in individual subgroups demonstrated the significance of caspase-3 expression in clinical outcomes in receptor positive (ER, PR or HER2) subgroups (P = 0.001) and in non-basal like subgroup (P = 0.029). Calpain expression had been previously assessed. Significant association was also found between high caspase-3/high calpain-1 and breast cancer-specific survival in the total patient cohort (P = 0.005) and basal-like subgroup (P = 0.034), as indicated by Kaplan-Meier analysis. Caspase-3 expression is associated with adverse breast cancer-specific survival in breast cancer patients, and provides additional prognostic values in distinct phenotypes. Combinatorial caspase and calpain expression can predict worse prognosis, especially in basal-like phenotypes. The findings warrant further validation studies in independent multi-centre patient cohorts.
authors: Division of Cancer and Stem Cells, Department of Clinical Oncology, School of Medicine, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK.
authors: Xuan
authors: X
authors: Pu
authors: Division of Cancer and Stem Cells, Department of Clinical Oncology, School of Medicine, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK.
authors: Sarah J
authors: SJ
authors: Storr
authors: Division of Cancer and Stem Cells, Department of Clinical Oncology, School of Medicine, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK.|Department of Breast and Thyroid Surgery, Renmin Hospital, Wuhan University, Wuhan, Hubei, China.
authors: Yimin
authors: Y
authors: Zhang
authors: Division of Cancer and Stem Cells, Department of Histopathology, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK.
authors: Emad A
authors: EA
authors: Rakha
authors: Division of Cancer and Stem Cells, Department of Histopathology, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK.
authors: Andrew R
authors: AR
authors: Green
authors: Division of Cancer and Stem Cells, Department of Histopathology, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK.
authors: Ian O
authors: IO
authors: Ellis
authors: Division of Cancer and Stem Cells, Department of Clinical Oncology, School of Medicine, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK. stewart.martin@nottingham.ac.uk.
authors: Stewart G
authors: SG
authors: Martin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000145:classification / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000032:analysis; D002154:Calpain / Q000032:analysis; D002277:Carcinoma / Q000145:classification / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D053148:Caspase 3 / Q000032:analysis*; D053181:Caspase 8 / Q000032:analysis*; D045744:Cell Line, Tumor; D004967:Estrogens; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D011374:Progesterone; D011379:Prognosis; D046888:Tissue Array Analysis; D055815:Young Adult
chemical_list: D002135:Calcium-Binding Proteins; D004967:Estrogens; D009363:Neoplasm Proteins; D011374:Progesterone; C033668:calpastatin; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D002154:Calpain; D053148:Caspase 3; D053181:Caspase 8
keywords: Biomarker; Breast cancer; Breast cancer-specific survival; Calpain; Caspase