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. 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.
Bibliographical noteFunding Information:
We thank Dr. John Letterio for critical reading of the manuscript. This work was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea ( 1520120 ). S.-J.K. is the recipient of a National Research Foundation of Korea grant ( NRF-2014M3A9B5073918 ) funded by the Ministry of Science, ICR & Future Planning. S.-J.K. is a shareholder in TheragenEtex .
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)