LAUSR

BACKGROUND GRP94 is a glucose-regulated protein critical for survival in endoplasmic reticulum stress. Expression of GRP94 is associated with cellular transformation and increased tumorigenicity in breast cancer. Specifically, over-expression of GRP94 predicts brain metastasis in breast carcinoma patients with either triple negative or ErbB2 positive tumors. The aim of this study was to understand if microenvironmental regulation of GRP94-expression might be a hinge orchestrating brain metastasis (BrM) progression. METHODS GRP94 ablation was performed in a BrM model BR-eGFP-CMV/Luc-V5CA1 (BRV5CA1) of breast cancer. In vitro results were validated in a data set of 29 metastases in diverse organs from human breast carcinomas and in BrM tissue from tumors of different primary origin. BrM patient-derived xenografts (PDX) were used to test sensitivity to the therapeutic approach. RESULTS BrM that over-express GRP94 as well as TRAF2 are more resistant to glucose deprivation by induction of anti-apoptotic proteins (BCL2 and IAPs) and engagement of pro-survival autophagy. GRP94 ablation down-regulated autophagy in tumor cells, resulting in decreased survival in vivo. These results were validated in a metastasis data set from human patients suggesting that targeting autophagy might be strategic for BrM prevention. Indeed, hydroxychloroquine treatment of preclinical models of BrM from PDX exerts preventive inhibition of tumor growth (p<0,001). CONCLUSIONS We show that GRP94 is directly implicated in BrM establishment by activating pro-survival autophagy. Disruption of this compensatory fueling route might prevent metastatic growth.