SGCE Promotes Breast Cancer Stem Cells by Stabilizing EGFR

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 CD24lowCD44high and high aldehyde dehydrogenase 1 (ALDH1) cell subpopulation (CD24lowCD44high ALDH1+) exhibit very high tumor initiating capacity. In the current study, the upregulated genes are analyzed in both CD24lowCD44high 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.