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.
Highlights
Chemotherapy can kill tumor cells in TNBC, it fails to eliminate Breast cancer stem cells (BCSCs), which may be the reason for recurrence and Breast cancer is the most commonly diagnosed cancer world- drug resistance.[6,7]wide and the leading cancer among women.[1]
Epidermal growth factor receptor (EGFR) expression in solid tumors, including breast cancer, is 20–50-fold higher than that reported in normal tissues,[10] and high EGFR expression is found in 69% of TNBC.[11]
We found SGCE to be highly expressed in BCSCs and closely related with BCSC self-renewal, tumorigenesis, and chemoresistance as well as extracellular matrix (ECM) deposition and remodeling
Summary
Chemotherapy can kill tumor cells in TNBC, it fails to eliminate BCSCs, which may be the reason for recurrence and Breast cancer is the most commonly diagnosed cancer world- drug resistance.[6,7]. Epidermal growth factor receptor (EGFR), which belongs to the receptor tyrosine kinase family,[8] is important for drug resistance, cancer stem cells, and metastasis in different types of cancer.[9] EGFR expression in solid tumors, including breast cancer, is 20–50-fold higher than that reported in normal tissues,[10] and high EGFR expression is found in 69% of TNBC.[11] treatment targeting EGFR, including inhibitors of EGFR (e.g., tyrosine kinase inhibitors, TKIs) and mAbs have been taken efforts. SGCE is the ε isoform member of the sarcoglycan family and includes transmembrane components in a dystrophin– glycoprotein complex. This complex helps to stabilize muscle fiber membranes and links the muscle cytoskeleton to the extracellular matrix (ECM). SGCE was involved in anti-EGFR resistance, which is implicated in targeted therapy for TNBC, providing new clues for deciphering the current failure of EGFR targeted therapies in clinical trials
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