Low cleaved caspase-7 levels indicate unfavourable outcome across all breast cancers
Elevated levels of the anti-apoptotic BCL2 protein associate with favourable outcome in breast cancer. We investigated whether executioner caspase activation downstream of mitochondrial apoptosis was associated with, or independent, of BCL2’s prognostic signature in breast cancer. Levels of pro- and anti-apoptotic BCL2 family proteins were quantified in triple negative breast cancer (TNBC) samples and utilised to calculate BCL2 profiles of 845 breast cancer patients. Biomarkers including single apoptosis proteins and network-enriched apoptosis system signatures were evaluated using uni- and multi-variate Cox-models. In both TNBC and non-TNBC breast cancer, the anti-apoptotic BCL2 protein was particularly abundant when compared to other solid tumours. High BCL2 protein levels were prognostic of favourable outcome across all breast cancers (HR 0.4, 95% CI 0.2–0.6, Wald p < 0.0001). Although BCL2 and cleaved caspase-7 levels were negatively correlated, levels of cleaved caspase-7 were also associated with favourable outcome (HR 0.4, 95% CI 0.3–0.7, Wald p = 0.001). A combination of low BCL2 and low cleaved caspase-7 protein levels was highly prognostic of unfavourable outcome across all breast cancers (HR 11.29, 95% CI 2.20–58.23, Wald p = 0.01). A combination of BCL2 and cleaved caspase-7 levels is a promising prognostic biomarker in breast cancer patients.
BCL2 levels are elevated in breast cancer where they are marker of good prognosis.
BCL2 and active caspase levels correlate negatively; yet, active caspases indicate good outcome.
Low BCL2 and low caspase-7 are highly prognostic of unfavourable outcome across all breast cancers.
BCL2 levels indicate molecular subtype and tumour proliferation status in breast cancer.
KeywordsBreast cancer BCL-2 proteins Apoptosis Cell death Caspases Systems biology
analysis of variance
- BAK, BCL2
antagonist/killer 1 (BAK1)
- BAX, BCL2
associated X, apoptosis regulator (BCL2L4)
B-cell lymphoma 2
B-cell lymphoma-extra large (BCL2L1)
Bcl-2 interacting mediator of cell death (BCL2L11)
BCL2 homology 3rd domain
oestrogen receptor 1 (ESR1)
Receptor tyrosine-protein kinase erbB-2 (ERBB2)
inhibitor of apoptosis
myeloid cell leukaemia sequence 1 (BCL2L3)
mitochondrial outer membrane permeabilisation
nanomolar (10−9 mol/L)
horbol-12-Myristate-13-Acetate-Induced protein 1 (PMAIP1)
proportional hazards assumption
progesterone receptor (PGR)
phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit
p53 upregulated modulator of apoptosis (BBC3)
reverse protein phase array
The Cancer Genome Atlas
triple negative breast cancer
tumour/lymph node/metastasis staging system
- Tukey HSD
Tukey Honest significant differences post-hoc test
voltage-dependent anion channel 2
- Wald p
Wald test probability value
We are grateful to the patients and their families who participated in this study. We thank Ciaran de Chaumont and Lance Hudson for technical assistance, Ramphul Eimear, Dr. Róisín M. Dwyer and Prof. Michael J. Kerin for sharing of samples, and Dr. Triona Ni Chonghaile for critical review of the manuscript. The results published here are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov which we also gratefully acknowledge.
A.U.L., F.L. and D.V. generated data. A.U.L. and A.R. performed data analysis. D.V., B.M.M., A.D.K.H. and L.S.Y. acquired clinical data and provided material. J.H.M.P. and W.M.G. conceived this study and provided funding. J.H.M.P. and L.S.Y. supervised the study. A.U.L. and J.H.M.P. wrote the manuscript. All authors read, reviewed and approved the final manuscript.
Funding support was provided by the Irish Cancer Society Collaborative Cancer Research Centre grant, BREAST-PREDICT (to J.H.M.P. and W.M.G.) and a Science Foundation Ireland Investigator Award to J.H.M.P. (13/IA/1881).
Compliance with ethical standards
Informed consents were collected following ethical approval from Beaumont Hospital Medical Research Ethics Committee.
Conflict of interest
AUL and JHMP filed a patent application at the EPO (Appl.No. EP20120166187 and EP20130728324), USPTO (Appl. No. 14/397697) and WIPO (Appl. No. PCT/EP2013/059051). The other authors declare no further conflict of interest.
Ethics approval and consent to participate
For the BREAST-PREDICT cohort, informed consents were collected following ethical approval from Beaumont Hospital Medical Research Ethics Committee.
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