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Theranostics 2021; 11(13):6355-6369. doi:10.7150/thno.51286 This issue Cite

Research Paper

DEPTOR stabilizes ErbB2 to promote the proliferation and survival of ErbB2-positive breast cancer cells

Yanli Bi1,2,3, Xiaoyu Chen1,2,3,8, Bajin Wei5, Linchen Wang1,2,3, Longyuan Gong1,2,3, Haomin Li6, Xiufang Xiong3,4, Yongchao Zhao1,2,3,7✉

1. Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
2. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
3. Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
4. Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
5. Department of Breast Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
6. Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
7. Cancer Center, Zhejiang University, Hangzhou, China.
8. Department of Medical Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

✉ Corresponding author: Yongchao Zhao, Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qing-Chun Road, Hangzhou, Zhejiang 310003, P. R. China. Tel. +86-571-86971963; E-mail: More

Citation:
Bi Y, Chen X, Wei B, Wang L, Gong L, Li H, Xiong X, Zhao Y. DEPTOR stabilizes ErbB2 to promote the proliferation and survival of ErbB2-positive breast cancer cells. Theranostics 2021; 11(13):6355-6369. doi:10.7150/thno.51286. https://www.thno.org/v11p6355.htm
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Abstract

Graphic abstract

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.

Keywords: ErbB2, DEPTOR, β-TrCP, PDZ, breast tumorigenesis

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APA
Bi, Y., Chen, X., Wei, B., Wang, L., Gong, L., Li, H., Xiong, X., Zhao, Y. (2021). DEPTOR stabilizes ErbB2 to promote the proliferation and survival of ErbB2-positive breast cancer cells. Theranostics, 11(13), 6355-6369. https://doi.org/10.7150/thno.51286.

ACS
Bi, Y.; Chen, X.; Wei, B.; Wang, L.; Gong, L.; Li, H.; Xiong, X.; Zhao, Y. DEPTOR stabilizes ErbB2 to promote the proliferation and survival of ErbB2-positive breast cancer cells. Theranostics 2021, 11 (13), 6355-6369. DOI: 10.7150/thno.51286.

NLM
Bi Y, Chen X, Wei B, Wang L, Gong L, Li H, Xiong X, Zhao Y. DEPTOR stabilizes ErbB2 to promote the proliferation and survival of ErbB2-positive breast cancer cells. Theranostics 2021; 11(13):6355-6369. doi:10.7150/thno.51286. https://www.thno.org/v11p6355.htm

CSE
Bi Y, Chen X, Wei B, Wang L, Gong L, Li H, Xiong X, Zhao Y. 2021. DEPTOR stabilizes ErbB2 to promote the proliferation and survival of ErbB2-positive breast cancer cells. Theranostics. 11(13):6355-6369.

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