Abstract 2826: BAG2 promotes tumorigenesis and metastasis by regulating the Cathepsin B cleavage in triple-negative breast cancer cells

Breast cancer is classified into clinical subtypes based upon receptor expression (ER, PR, Her2). Among the breast cancer subtypes, triple-negative breast cancer (TNBC) refers to a form of breast cancer which lacks expression of ER, PR and HER2. Most of breast cancer treatments can be targeted for cancers that express hormonal receptors or HER2, whereas traditional chemotherapy does not work in TNBCs. Therefore, TNBC remains a clinical challenge for discovery novel specific target biomarker because of no targeted therapies for TNBC. In this study, we show that BAG2 promotes cancer progression by regulating the dual function of Cathepsin B in TNBC cells. We found that BAG2 is highly expressed in basal-like breast cancer cells, where it was associated with recurrence or distant metastasis-free survival in patients. In loss-of-function experiment, BAG2 knockdown strongly decreased the ability of tumor formation and lung metastasis in vivo in TNBC cells. Mechanistically, BAG2 induces metastasis through regulation of secretion of pro-form Cathepsin B and prevents lysosome-mediated cell death through decrease of intracellular single-chain form of Cathepsin B into cytoplasm. Thus, our results suggest that BAG2 promotes tumorigenesis and metastasis through regulation of Cathepsin B cleavage in TNBC cells and may be possible as a novel specific target for treatment of TNBC. [This work was supported by National RD 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2826.