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

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.

The faciogenital dysplasia gene FGD5 is differentially expressed in non-small cell lung cancer and associates with patient survival.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the United States (1). We mined published microarray data (2, 3, 4) to identify differentially expressed genes in NSCLC. We found that the gene encoding the faciogenital dysplasia gene 5, FGD5, was among the genes whose expression was most quantitatively different in tumors from patients with NSCLC as compared to the lung. FGD5 expression was significantly decreased in NSCLC tumors as compared to the lung, and lower expression of FGD5 in patient tumors was significantly associated with worse overall survival. FGD5 may be important for initiation or progression of non-small cell lung cancer in humans.

Minireview: Role of genetic changes of faciogenital dysplasia protein 1 in human disease

The FGD1 gene encodes for a guanine exchange factor (GEF) protein that specifically activates the Rho GTPase Cdc42. For cellular migration, Cdc42 is a key molecular switch that regulates cytoskeleton restructuring, gene transcription, cellular morphology, extension, and cell adhesion. In the past decade, germline mutations in the FGD1 gene have been associated with a rare X-linked disorder known as faciogenital dysplasia (FGDY). Malformations are consistent with a loss of cellular migration during embryonic development. Insertion and deletion mutations in FGD1 result in a frameshift causing inactivation of fgd1 protein. Since Cdc42 is a key molecular switch in cytoskeletal restructuring and cell adhesion, the loss of fgd1 is postulated to attenuate Cdc42-mediated cellular migration in embryonic development. In metastatic tumors, Cdc42 modulates migration and invasiveness. Fgd1 overexpression has been found in infiltrating and poorly differentiated breast and invasive prostate tumors. Amplification at Xp11.21, the FGD1 gene locus, has been reported in several cancers. Sequencing analyses in numerous types of cancer have found missense mutations in the FGD1 gene in metastatic tumors. FGDY and cancer studies suggest that the germline and somatic changes downregulate or upregulate the FGD1 gene playing a key role in the development of diseases.