Research ArticleCancer

Faciogenital Dysplasia 5 supports cancer stem cell traits in basal-like breast cancer by enhancing EGFR stability

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Science Translational Medicine  24 Mar 2021:
Vol. 13, Issue 586, eabb2914
DOI: 10.1126/scitranslmed.abb2914

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PERfecting breast cancer treatment

Basal-like breast cancers are associated with a poorer prognosis, and there are no targeted therapies. Li et al. examined Faciogenital Dysplasia 5 (FGD5) in basal-like breast cancer, finding that FGD5 supported tumor initiation by reducing epidermal growth factor receptor (EGFR) ubiquitination and degradation, leading to increased invasiveness and self-renewal. The authors developed a peptide, PER3, to reduce the interaction between EGFR and FGD5. PER3 treatment suppressed growth of tumors displaying high EGFR and FGD5 abundance in mice and resensitized resistant tumors to paclitaxel. Although further studies are needed to determine the safety of PER3, FGD5 is a promising target for the treatment of basal-like breast cancers.


Most basal-like breast cancers (BLBCs) are triple-negative breast cancers (TNBCs), which have the worst prognosis and distant metastasis-free survival among breast cancer subtypes. Now, no targeted therapies are available for patients with BLBC due to the lack of reliable and effective molecular targets. Here, we performed the BLBC tissue microarray–based immunohistochemical analysis and showed that Faciogenital Dysplasia 5 (FGD5) abundance is associated with poor prognosis in BLBCs. FGD5 deletion decreased the proliferation, invasion, and tumorsphere formation capacity of BLBC cells. Furthermore, genetic inhibition of Fgd5 in mouse mammary epithelial cells attenuated BLBC initiation and progression by reducing the self-renewal ability of tumor-initiating cells. In addition, FGD5 abundance was positively correlated with the abundance of epidermal growth factor receptor (EGFR) in BLBCs. FGD5 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.

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