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

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

21 ( 10 )  , pp.2952 - 2964 , 2017-12 , Elsevier (Cell Press)
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.

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