Role of FOXQ1 in proliferation and progression of breast cancer cells promoted by FGFR1 signaling

Abstract

Breast cancer is the most common cancer in women and represents a public health problem. Breast cancer cell growth is supported by many deregulated signaling pathways, including the fibroblast growth factor receptor 1 (FGFR1). FGFR1 is a receptor tyrosine kinase deregulated in certain breast cancers with a poor prognosis. Although FGFR1-activated phosphorylation cascades have been mapped, the key genes regulated by FGFR1 in breast cancer are largely unclear. Forkhead box Q1 (FOXQ1) is an oncogenic transcription factor. Although activation of FGFR1 was found to upregulate FOXQ1 mRNA robustly, how FGFR1 regulates FOXQ1 gene expression and whether FOXQ1 is essential for FGFR1-stimulated cell proliferation are unknown. This study confirmed that activation of FGFR1 robustly upregulated FOXQ1 mRNA and protein levels in breast cancer cells. Knockdown of FOXQ1 blocked the FGFR1 signaling-stimulated breast cancer cell proliferation, colony formation, and xenograft tumor growth. Inhibition of MEK or ERK1/2 activities, or knockout of ERK2 but not ERK1 suppressed the FGFR1 signaling-promoted FOXQ1 gene expression. Inhibition of ERK2 in ERK1 knockout cells blocked, while ectopic expression of FOXQ1 in ERK2 knockout cells rescued the FGFR1-signaling-promoted cell growth. Mechanistically, c-FOS, an early response transcription factor upregulated by the FGFR1-MEK-ERK2 pathway, bound to the FOXQ1 promoter to mediate the FGFR1 signaling-promoted FOXQ1 expression. These results indicate that the FGFR1-ERK2-c-FOS-FOXQ1 regulatory axis is essential in the FGFR1 signaling-promoted breast cancer growth. Targeting ERK2 and FOXQ1 should block breast cancer growth caused by a deregulated FGFR1 signaling. In addition, DCIS-iFGFR1 cells with FOXQ1 depletion exhibited an epithelioid phenotype. Its capability of migration and invasion markedly went down. Vimentin expression in FOXQ1-knockdown cells decreased. All these results indicate that FOXQ1 is an essential factor in the epithelial-mesenchymal transition of DCIS-iFGFR1 cells. FOXQ1 might serve as a target for blocking the malignancy progression of breast cancer.