Co-chaperone BAG2 Determines the Pro-oncogenic Role of Cathepsin B in Triple-Negative Breast Cancer Cells

• Published in: Cell reports (Cambridge) 2017-12, Vol.21 (10), p.2952-2964
• Main Authors: Yang, Kyung-Min, Bae, Eunjin, Ahn, Sung Gwe, Pang, Kyoungwha, Park, Yuna, Park, Jinah, Lee, Jihee, Ooshima, Akira, Park, Bora, Kim, Junil, Jung, Yunshin, Takahashi, Satoru, Jeong, Joon, Park, Seok Hee, Kim, Seong-Jin
• Format: Article
• Language: English
• Subjects: Apoptosis - genetics; Apoptosis - physiology; BAG2; breast cancer; Breast Neoplasms - metabolism; cathepsin B; Cathepsin B - genetics; Cathepsin B - metabolism; Cell Line, Tumor; Female; Humans; metastasis; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; TGN38; TNBC; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; tumorigenesis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.11.026

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. [Display omitted] •BAG2 overexpression in TNBC is strongly correlated with poor clinical outcomes•BAG2 regulates auto-cleavage of pro-cathepsin B by binding to the propeptide region•Silencing BAG2 induces apoptosis through increase of single-chain cathepsin B•BAG2 controls the secretion of pro-CTSB through TGN38-positive vesicles The mechanisms controlling the pro- and anti-oncogenic roles of cathepsin B are unclear. Yang et al. find that BAG2 is a regulator of the dual functions of its client protein, CTSB, facilitating the progression of TNBC.