The pro-apoptotic paradox: the BH3-only protein Bcl-2 interacting killer (Bik) is prognostic for unfavorable outcomes in breast cancer.
Breast cancer is the leading cause of cancer-associated deaths in women worldwide. Clinical biomarkers give information on disease progression and identify relevant biological pathways. A confounding factor that uncouples markers from disease outcome is the ability of tumor cells to mutate and evade clinical intervention. Therefore, we focussed on apoptotic genes that modulate tumor regression. Using gene and tissue microarray analyses, we identified an association of Bcl-2 interacting killer (Bik) with poor breast cancer prognosis. Bik prognostic ability was independent of Estrogen Receptor/Progesterone Receptor and Her2 status. Additionally, Bik was independent of anti-apoptotic Bcl-2, Bcl-xL, Mcl-1 and Bcl-w suggesting a complex mechanism of tumor promotion identified by Bik high tumors. Bik also stimulates autophagy, which can contribute to enhanced tumor fitness. We found a significant association between the autophagy marker ATG5 and Bik. Combined high expression level of ATG5 and Bik was a stronger predictor of outcome than either alone. Thus, our study identifies Bik as a novel, independent prognostic biomarker for poor outcomes in breast cancer and suggests that Bik-mediated autophagy contributes to disease recurrence.
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Vrajesh
V
Pandya
Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Darryl
D
Glubrecht
Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Larissa
L
Vos
Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
John
J
Hanson
Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Sambasivarao
S
Damaraju
Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
John
J
Mackey
Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Judith
J
Hugh
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.|Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Ing Swie
IS
Goping
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000032:analysis* / Q000235:genetics; D001343:Autophagy; D000071187:Autophagy-Related Protein 5 / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001943:Breast Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D053208:Kaplan-Meier Estimate; D008565:Membrane Proteins / Q000032:analysis* / Q000235:genetics; D008875:Middle Aged; D024101:Mitochondrial Proteins; D009364:Neoplasm Recurrence, Local; D020411:Oligonucleotide Array Sequence Analysis; D016016:Proportional Hazards Models; D012307:Risk Factors; D013997:Time Factors; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D015854:Up-Regulation
C502778:ATG5 protein, human; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C096820:BIK protein, human; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D024101:Mitochondrial Proteins
BH3-only proteins; Bcl-2 interacting killer; BiK; autophagy; breast cancer