Faciogenital Dysplasia 5 supports cancer stem cell traits in basal-like breast cancer by enhancing EGFR stability
Ke Li, Tingting Zhang, Chenxi Zhao, Feng Wang, Bing Cui, Zhao-na Yang, Xiaoxi Lv, Zaiwuli Yeerjiang, Yufen Yuan, Jinmei Yu, Zhenhe Wang, Xiaowei Zhang, Jiaojiao Yu, Shan-shan Liu, Shuang Shang, Bo Huang, Fang Hua, Zhuowei Hu
Abstract
ablation decreased EGFR abundance by reducing EGFR stability in TNBC cells in 2D and 3D culture conditions. Mechanistically, FGD5 binds to EGFR and interferes with basal EGFR ubiquitination and degradation induced by the E3 ligase ITCH. Impaired EGFR degradation caused BLBC cell proliferation and promoted invasive properties and self-renewal. To verify the role of the FGD5-EGFR interaction in the regulation of EGFR stability, we screened a cell-penetrating α-helical peptide PER3 binding with FGD5 to disrupt the interaction. Treatment of BLBC patient-derived xenograft-bearing mice with the peptide PER3 disrupting the FGD5-EGFR interaction either with or without chemotherapy reduced BLBC progression. Our study identified FGD5 as a positive modulator of tumor-initiating cells and suggests a potential therapeutic option for the BLBC subtype of breast cancer.