SGCE Promotes Breast Cancer Stem Cells by Stabilizing EGFR

Area of Science:

• Oncology
• Molecular Biology
• Cancer Stem Cell Research

Background:

• Breast cancer stem cells (BCSCs) drive therapeutic resistance, metastasis, and poor outcomes, particularly in triple-negative breast cancer (TNBC).
• Specific subpopulations like CD24lowCD44high ALDH1+ cells exhibit high tumor-initiating potential.
• Identifying novel targets within BCSCs is crucial for improving treatment efficacy.

Purpose of the Study:

• To identify key genes and proteins upregulated in BCSCs.
• To investigate the role of the identified protein, SGCE, in BCSC function and therapeutic resistance.
• To elucidate the molecular mechanism by which SGCE influences BCSC stemness and signaling pathways.

Main Methods:

• Single-cell resolution analysis of gene expression in CD24lowCD44high and ALDH1+ BCSC populations.
• In vitro and in vivo experiments to assess the effects of SGCE depletion on BCSC self-renewal, chemoresistance, and metastasis.
• Investigation of SGCE's interaction with epidermal growth factor receptor (EGFR) and its ubiquitination ligase (c-Cbl).

Main Results:

• SGCE was identified as a highly expressed membrane protein in both CD24lowCD44high and ALDH1+ BCSCs.
• SGCE depletion significantly reduced BCSC self-renewal, chemoresistance, and metastasis.
• SGCE was found to stabilize EGFR by inhibiting its lysosomal degradation, acting as a molecular sponge for EGFR and c-Cbl interaction.
• SGCE knockdown enhanced sensitivity to EGFR tyrosine kinase inhibitors (TKIs).

Conclusions:

• SGCE is a critical regulator of breast cancer stemness, chemoresistance, and metastasis.
• Targeting SGCE offers a potential therapeutic strategy to overcome resistance in TNBC.
• Understanding SGCE's role in EGFR stabilization provides insights into current treatment failures and suggests novel therapeutic approaches.