Journal
CELL REPORTS
Volume 21, Issue 10, Pages 2952-2964Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.11.026
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Funding
- National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea [1520120]
- National Research Foundation of Korea - Ministry of Science, ICR & Future Planning [NRF-2014M3A9B5073918]
- National Research Foundation of Korea [2014M3A9B5073918] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 procathepsin B and a potential diagnostic and therapeutic target that may reduce the burden of metastatic breast cancer.
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