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

Syeda Kiran Riaz,Tanwir Khaliq,Jahangir Sarwar Khan,Muhammad Faraz Arshad Malik,Steve Harakeh,Fen Wang,Shadi S Alkhayyat,Shafiul Haque,Mohammad Javed Ansari,Najiah Esam Azhar,Anwar M Hashem,Eisha Tir Razia,Amber Malik,Farhan Haq,Walizeb Khan

doi:10.3389/fcell.2021.758400

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.

Highlights

The fibroblast growth factor receptor (FGFR) signaling pathway plays an important role in a variety of biological processes including angiogenesis, cell growth, differentiation, and survival (Korc and Friesel, 2009; Wesche et al, 2011)
We evaluated the effect of SHH and GLI1 expression in mouse embryonic fibroblasts (MEFs) with MEFFGFR WT and MEFFGFR1 KO cells
FGFR1 is a known poor prognostic marker associated with poor survival in breast cancer patients (Wu et al, 2018)

Summary

Introduction

The fibroblast growth factor receptor (FGFR) signaling pathway plays an important role in a variety of biological processes including angiogenesis, cell growth, differentiation, and survival (Korc and Friesel, 2009; Wesche et al, 2011). The genetic aberrations in FGFs and FGFRs linked to tumor initiation and progression are extensively reported in many cancers (Parish et al, 2015). 23 different FGFs have been identified, out of which 18 ligands (FGF1–10 and 16–23) are mitogenic signaling molecules (Beenken and Mohammadi, 2009) These FGFs bind and activate FGFRs (1–4), highly conserved tyrosine kinase receptors, to modulate other signaling pathways (Kwabi-Addo et al, 2004; Babina and Turner, 2017), including PLCγ/DAG/PKC, PI3K/AKT, RAS/RAF, and MAPK (Dienstmann et al, 2014; Ornitz and Itoh, 2015). Studies are underway to identify FGFR1-linked gene set(s) to devise effective breast cancer treatment options. The aim of the current study was to identify FGFR1-linked gene sets to devise effective breast cancer treatment options. The current study provides new FGFR1-linked biomarkers, which suggest novel treatment options for improving the prognosis of breast cancer patients

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