SGCE Promotes Breast Cancer Stem Cells by Stabilizing EGFR

Lina Zhao; Ting Qiu; Dewei Jiang; Haibo Xu; Li Zou; Qin Yang; Ceshi Chen; Baowei Jiao

doi:10.1002/advs.201903700

SGCE Promotes Breast Cancer Stem Cells by Stabilizing EGFR

Adv Sci (Weinh). 2020 Jun 8;7(14):1903700. doi: 10.1002/advs.201903700. eCollection 2020 Jul.

Authors

Lina Zhao^{1

2}, Ting Qiu^{2

3}, Dewei Jiang³, Haibo Xu^{1

2}, Li Zou¹, Qin Yang¹, Ceshi Chen^{3

4}, Baowei Jiao^{1

4

5}

Affiliations

¹ State Key Laboratory of Genetic Resources and Evolution Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan 650223 China.
² Kunming College of Life Science University of Chinese Academy of Sciences Kunming Yunnan 650223 China.
³ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan 650223 China.
⁴ KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan 650223 China.
⁵ Center for Excellence in Animal Evolution and Genetics Chinese Academy of Sciences Kunming Yunnan 650223 China.

Abstract

Breast cancer stem cells (BCSCs) are responsible for resistance to chemotherapy, high degree of metastasis, and poor prognosis, especially in triple-negative breast cancer (TNBC). The CD24^lowCD44^high and high aldehyde dehydrogenase 1 (ALDH1) cell subpopulation (CD24^lowCD44^high ALDH1⁺) exhibit very high tumor initiating capacity. In the current study, the upregulated genes are analyzed in both CD24^lowCD44^high and ALDH1⁺ cell populations at single-cell resolution, and a highly expressed membrane protein, SGCE, is identified in both BCSC populations. Further results show that SGCE depletion reduces BCSC self-renewal, chemoresistance, and metastasis both in vitro and in vivo, partially through affecting the accumulation of extracellular matrix (ECM). For the underlying mechanism, SGCE functions as a sponge molecule for the interaction between epidermal growth factor receptor (EGFR) and its E3 ubiquitination ligase (c-Cbl), and thus inhibits EGFR lysosomal degradation to stabilize the EGFR protein. SGCE knockdown promotes sensitivity to EGFR tyrosine kinase inhibitors (TKIs), providing new clues for deciphering the current failure of targeting EGFR in clinical trials and highlighting a novel candidate for BCSC stemness regulation.

Keywords: SGCE; breast cancer stem cells; epidermal growth factor receptors.