Search

Rationale: Dysregulation of the PI3K/AKT/mTOR pathway occurs frequently in cancers, providing an attractive therapeutic target for anticancer treatments. DEPTOR plays essential roles in regulation of cell proliferation and survival by directly modulating mTOR activity. However, whether DEPTOR regulates the growth of ErbB2-positive breast cancer cells remains unknown. Methods: DEPTOR expression was determined by TCGA data analysis and immunohistochemistry of human breast tissue microarrays. The membrane localization of DEPTOR was demonstrated by immunofluorescence and subcellular fractionation. The interaction of DEPTOR with ErbB2 was determined by immunoprecipitation. Furthermore, the biological significance of this interaction was assessed by ATPlite cell growth, clonogenic survival, and flow cytometry-based apoptosis assays. Results: DEPTOR promoted the proliferation and survival of ErbB2-positive breast cancer cells by directly interacting with and stabilizing ErbB2. Specifically, DEPTOR translocates to cell membrane and interacts with ErbB2 to disrupt ErbB2 polyubiquitination and degradation promoted by β-TrCP, an E3 ubiquitin ligase. DEPTOR knockdown destabilizes ErbB2 by shortening its protein half-life to inactivate ErbB2-PI3K-AKT-mTOR signaling, leading to the suppression of cell proliferation and survival by inducing apoptosis. Ectopic expression of a constitutively active ErbB2 mutant completely rescued the reduction in cell proliferation and survival by DEPTOR knockdown. Importantly, DEPTOR expression is increased in human breast cancer tissues and its overexpression correlates with poor patient survival. Moreover, DEPTOR is located on the cell membrane in ErbB2-positive breast cancer tissues, but not in tumor-adjacent normal tissues, indicating that DEPTOR may contribute to the oncogenic characteristics of ErbB2. Conclusions: Our study reveals a novel mechanism by which DEPTOR promotes breast cancer cell proliferation and survival by stabilizing ErbB2.