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.