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Targeted Inhibition of Fibroblast Growth Factor Receptor 1-GLI Through AZD4547 and GANT61 Modulates Breast Cancer Progression
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 t...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548881/ https://www.ncbi.nlm.nih.gov/pubmed/34722544 http://dx.doi.org/10.3389/fcell.2021.758400 |
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author | 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 |
author_facet | 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 |
author_sort | Riaz, Syeda Kiran |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8548881 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85488812021-10-28 Targeted Inhibition of Fibroblast Growth Factor Receptor 1-GLI Through AZD4547 and GANT61 Modulates Breast Cancer Progression 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 Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2021-10-13 /pmc/articles/PMC8548881/ /pubmed/34722544 http://dx.doi.org/10.3389/fcell.2021.758400 Text en Copyright © 2021 Riaz, Khan, Wang, Khaliq, Malik, Razia, Khan, Haque, Hashem, Alkhayyat, Azhar, Harakeh, Ansari, Haq and Malik. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology 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 Targeted Inhibition of Fibroblast Growth Factor Receptor 1-GLI Through AZD4547 and GANT61 Modulates Breast Cancer Progression |
title | Targeted Inhibition of Fibroblast Growth Factor Receptor 1-GLI Through AZD4547 and GANT61 Modulates Breast Cancer Progression |
title_full | Targeted Inhibition of Fibroblast Growth Factor Receptor 1-GLI Through AZD4547 and GANT61 Modulates Breast Cancer Progression |
title_fullStr | Targeted Inhibition of Fibroblast Growth Factor Receptor 1-GLI Through AZD4547 and GANT61 Modulates Breast Cancer Progression |
title_full_unstemmed | Targeted Inhibition of Fibroblast Growth Factor Receptor 1-GLI Through AZD4547 and GANT61 Modulates Breast Cancer Progression |
title_short | Targeted Inhibition of Fibroblast Growth Factor Receptor 1-GLI Through AZD4547 and GANT61 Modulates Breast Cancer Progression |
title_sort | targeted inhibition of fibroblast growth factor receptor 1-gli through azd4547 and gant61 modulates breast cancer progression |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548881/ https://www.ncbi.nlm.nih.gov/pubmed/34722544 http://dx.doi.org/10.3389/fcell.2021.758400 |
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