Targeted Inhibition of Fibroblast Growth Factor Receptor 1-GLI Through AZD4547 and GANT61 Modulates Breast Cancer Progression

Abstract

The underlying mechanism of fibroblast growth factor receptor 1 (FGFR1) mediated carcinogenesis is still not fully understood. For instance, FGFR1 upregulation leads to endocrine therapy resistance in breast cancer patients. The current study aimed to identify FGFR1-linked genes to devise improved therapeutic strategies. RNA-seq and microarray expression data of 1,425 breast cancer patients from two independent cohorts were downloaded for the analysis. Gene Set Enrichment Analysis (GSEA) was performed to identify differentially expressed pathways associated with FGFR1 expression. Validation was done using 150 fresh tumor biopsy samples of breast cancer patients. The clinical relevance of mRNA and protein expression of FGFR1 and its associated genes were also evaluated in mouse embryonic fibroblasts (MEFs) and breast cancer cell line (MDA-MB-231). Furthermore, MDA-MB-231 cell line was treated with AZD4547 and GANT61 to identify the probable role of FGFR1 and its associated genes on cells motility and invasion. According to GSEA results, SHH pathway genes were significantly upregulated in FGFR1 patients in both discovery cohorts of breast cancer. Statistical analyses using both discovery cohorts and 150 fresh biopsy samples revealed strong association of FGFR1 and GLI1, a member of SHH pathway. The increase in the expression of these molecules was associated with poor prognosis, lymph node involvement, late stage, and metastasis. Combined exposures to AZD4547 (FGFR1 inhibitor) and GANT61 (GLI1 inhibitor) significantly reduced cell proliferation, cell motility, and invasion, suggesting molecular crosstalk in breast cancer progression and metastasis. A strong positive feedback mechanism between FGFR1–GLI1 axis was observed, which significantly increased cell proliferation and metastasis. Targeting FGFR1–GLI1 simultaneously will significantly improve the prognosis of breast cancer in patients.

FGFR families: biological functions and therapeutic interventions in tumors

“…139 FGFR1 has been reported to enhance the expression of vascular endothelial growth factor A through tumor necrosis factor alpha-induced protein 3, thus contributing to breast cancer angiogenesis. 140 By gene set enrichment analysis, Riaz et al 141 found that FGFR1 is strongly correlated with GLI1 family zinc finger 1 (GLI1), a member of the Sonic hedgehog (SHH) pathway, and that the FGFR/GLI1 axis significantly promotes the metastasis of tumor cells. Furthermore, nuclear FGFR1, interacting with RNA-Polymerase II (Pol II) and forkhead box protein A1 (FOXA1), regulates the transcription of target genes, which is a process independent of tyrosine kinase activity and mediates resistance of ER+ breast cancer cells to estrogen inhibitors and fulvestrant.…”

“…FGFR1 has been reported to enhance the expression of vascular endothelial growth factor A through tumor necrosis factor alpha‐induced protein 3, thus contributing to breast cancer angiogenesis 140 . By gene set enrichment analysis, Riaz et al 141 . found that FGFR1 is strongly correlated with GLI1 family zinc finger 1 (GLI1), a member of the Sonic hedgehog (SHH) pathway, and that the FGFR/GLI1 axis significantly promotes the metastasis of tumor cells.…”

Precision unveiled: Synergistic genomic landscapes in breast cancer—Integrating single‐cell analysis and decoding drug toxicity for elite prognostication and tailored therapeutics

“…32 Similarly, overexpression of BST-2 has potential implications in breast cancer onset, 33 while FGFR1 overexpression substantially interferes with endocrine therapy, fostering resistance. 30,31,34 Another gene, SNRPD1, augments tumorigenicity via cell cycle modulation. 35 However, most prognostic models utilize these genes singularly, focusing on a specific gene set.…”

“…This includes UNC5B, which, when overexpressed, amplifies breast cancer cell proliferation, consequently dampening prognosis 32 . Similarly, overexpression of BST‐2 has potential implications in breast cancer onset, 33 while FGFR1 overexpression substantially interferes with endocrine therapy, fostering resistance 30,31,34 . Another gene, SNRPD1, augments tumorigenicity via cell cycle modulation 35 .…”