Riaz Syeda Kiran, Khan Walizeb, Wang Fen, Khaliq Tanwir, Malik Amber, Razia Eisha Tir, Khan Jahangir Sarwar, Haque Shafiul, Hashem Anwar M, Alkhayyat Shadi S, Azhar Najiah Esam, Harakeh Steve, Ansari Mohammad Javed, Haq Farhan, Malik Muhammad Faraz Arshad
Department of Biosciences, COMSATS University, Islamabad, Pakistan.
Department of Molecular Biology and Biochemistry, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
Front Cell Dev Biol. 2021 Oct 13;9:758400. doi: 10.3389/fcell.2021.758400. eCollection 2021.
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.
成纤维细胞生长因子受体1（FGFR1）介导的致癌作用的潜在机制仍未完全明确。例如，FGFR1上调会导致乳腺癌患者出现内分泌治疗耐药。当前研究旨在鉴定与FGFR1相关的基因，以设计出更好的治疗策略。下载了来自两个独立队列的1425例乳腺癌患者的RNA测序和微阵列表达数据用于分析。进行基因集富集分析（GSEA）以鉴定与FGFR1表达相关的差异表达通路。使用150例乳腺癌患者的新鲜肿瘤活检样本进行验证。还在小鼠胚胎成纤维细胞（MEF）和乳腺癌细胞系（MDA-MB-231）中评估了FGFR1及其相关基因的mRNA和蛋白表达的临床相关性。此外，用AZD4547和GANT61处理MDA-MB-231细胞系，以确定FGFR1及其相关基因对细胞运动性和侵袭的可能作用。根据GSEA结果，在乳腺癌的两个发现队列中，FGFR1患者的SHH通路基因均显著上调。使用发现队列和150例新鲜活检样本进行的统计分析显示，FGFR1与SHH通路成员GLI1之间存在强关联。这些分子表达的增加与预后不良、淋巴结受累、晚期和转移相关。联合使用AZD4547（FGFR1抑制剂）和GANT61（GLI1抑制剂）可显著降低细胞增殖、细胞运动性和侵袭，提示在乳腺癌进展和转移中存在分子串扰。观察到FGFR-1-GLI1轴之间存在强大的正反馈机制，这显著增加了细胞增殖和转移。同时靶向FGFR1-GLI1将显著改善乳腺癌患者的预后。
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