The pro-apoptotic paradox: the BH3-only protein Bcl-2 interacting killer (Bik) is prognostic for unfavorable outcomes in breast cancer

Abstract

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.