Co-chaperone BAG2 Determines the Pro-oncogenic Role of Cathepsin B in Triple-Negative Breast Cancer Cells.
Authors
Kyung-Min Yang ; Eunjin Bae ; Sung Gwe Ahn ; Kyoungwha Pang ; Yuna Park ; Jinah Park ; Jihee Lee ; Akira Ooshima ; Bora Park ; Junil Kim ; Yunshin Jung ; Satoru Takahashi ; Joon Jeong ; Seok Hee Park ; Seong-Jin Kim
BAG2 ; TGN38 ; TNBC ; breast cancer ; cathepsin B ; metastasis ; tumorigenesis
Abstract
Triple-negative breast cancer (TNBC) is considered incurable with currently available treatments, highlighting the need for therapeutic targets and predictive biomarkers. Here, we report a unique role for Bcl-2-associated athanogene 2 (BAG2), which is significantly overexpressed in TNBC, in regulating the dual functions of cathepsin B as either a pro- or anti-oncogenic enzyme. Silencing BAG2 suppresses tumorigenesis and lung metastasis and induces apoptosis by increasing the intracellular mature form of cathepsin B, whereas BAG2 expression induces metastasis by blocking the auto-cleavage processing of pro-cathepsin B via interaction with the propeptide region. BAG2 regulates pro-cathepsin B/annexin II complex formation and facilitates the trafficking of pro-cathespin-B-containing TGN38-positive vesicles toward the cell periphery, leading to the secretion of pro-cathepsin B, which induces metastasis. Collectively, our results uncover BAG2 as a regulator of the oncogenic function of pro-cathepsin B and a potential diagnostic and therapeutic target that may reduce the burden of metastatic breast cancer.