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FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells

Abnormal FGFR1 alternative splicing is correlated with tumorigenicity and poor prognosis in several tumor types. We sought to determine the roles of FGFR1α and FGFR1β variants in breast cancer. TCGA samples and cell lines were analyzed for FGFR1α/FGFR1β expression. MCF-10A cells were used to overexp...

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Autores principales: Zhao, Ming, Zhuo, Ming-Lei, Zheng, Xiaofeng, Su, Xiaoping, Meric-Bernstam, Funda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343755/
https://www.ncbi.nlm.nih.gov/pubmed/30713601
http://dx.doi.org/10.18632/oncotarget.26530
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author Zhao, Ming
Zhuo, Ming-Lei
Zheng, Xiaofeng
Su, Xiaoping
Meric-Bernstam, Funda
author_facet Zhao, Ming
Zhuo, Ming-Lei
Zheng, Xiaofeng
Su, Xiaoping
Meric-Bernstam, Funda
author_sort Zhao, Ming
collection PubMed
description Abnormal FGFR1 alternative splicing is correlated with tumorigenicity and poor prognosis in several tumor types. We sought to determine the roles of FGFR1α and FGFR1β variants in breast cancer. TCGA samples and cell lines were analyzed for FGFR1α/FGFR1β expression. MCF-10A cells were used to overexpress these variants. Cell growth and transformation were assessed by SRB, colony formation, 3D-Matrigel, soft agar, cell motility assays. In TCGA, compared to FGFR1 non-amplified samples, FGFR1-amplified samples had significantly higher FGFR1α but not FGFR1β levels. FGFR1β expression levels and FGFR1β/FGFR1α ratio were higher in basal subtype samples than in ER-positive/luminal samples in both TCGA and breast cancer cell lines. Both FGFR1α and FGFR1β induced transformation of MCF-10A cells. However, only FGFR1β-expressing cells, not FGFR1α, enhanced cell growth and cell motility. Cells with higher FGFR1β levels and FGFR1β/FGFR1α ratio were more sensitive to FGFR inhibitor BGJ-398. Interestingly, in ER-negative cells, FGFR inhibitors decreased FGFR1β levels, likely by increasing expression of splicing repressor PTBP1. In ER-positive cells, estrogen treatment increased FGFR1β levels by decreasing PTBP1 expression, which was blocked by 4-OHT. Lastly, combination treatment with BGJ-398 and 4-OHT synergistically inhibited cell survival. These findings suggest that FGFR1 alternative FGFR1α/FGFR1β splicing plays an important role in breast cancer.
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spelling pubmed-63437552019-02-01 FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells Zhao, Ming Zhuo, Ming-Lei Zheng, Xiaofeng Su, Xiaoping Meric-Bernstam, Funda Oncotarget Research Paper Abnormal FGFR1 alternative splicing is correlated with tumorigenicity and poor prognosis in several tumor types. We sought to determine the roles of FGFR1α and FGFR1β variants in breast cancer. TCGA samples and cell lines were analyzed for FGFR1α/FGFR1β expression. MCF-10A cells were used to overexpress these variants. Cell growth and transformation were assessed by SRB, colony formation, 3D-Matrigel, soft agar, cell motility assays. In TCGA, compared to FGFR1 non-amplified samples, FGFR1-amplified samples had significantly higher FGFR1α but not FGFR1β levels. FGFR1β expression levels and FGFR1β/FGFR1α ratio were higher in basal subtype samples than in ER-positive/luminal samples in both TCGA and breast cancer cell lines. Both FGFR1α and FGFR1β induced transformation of MCF-10A cells. However, only FGFR1β-expressing cells, not FGFR1α, enhanced cell growth and cell motility. Cells with higher FGFR1β levels and FGFR1β/FGFR1α ratio were more sensitive to FGFR inhibitor BGJ-398. Interestingly, in ER-negative cells, FGFR inhibitors decreased FGFR1β levels, likely by increasing expression of splicing repressor PTBP1. In ER-positive cells, estrogen treatment increased FGFR1β levels by decreasing PTBP1 expression, which was blocked by 4-OHT. Lastly, combination treatment with BGJ-398 and 4-OHT synergistically inhibited cell survival. These findings suggest that FGFR1 alternative FGFR1α/FGFR1β splicing plays an important role in breast cancer. Impact Journals LLC 2019-01-01 /pmc/articles/PMC6343755/ /pubmed/30713601 http://dx.doi.org/10.18632/oncotarget.26530 Text en Copyright: © 2019 Zhao et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Zhao, Ming
Zhuo, Ming-Lei
Zheng, Xiaofeng
Su, Xiaoping
Meric-Bernstam, Funda
FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells
title FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells
title_full FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells
title_fullStr FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells
title_full_unstemmed FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells
title_short FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells
title_sort fgfr1β is a driver isoform of fgfr1 alternative splicing in breast cancer cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343755/
https://www.ncbi.nlm.nih.gov/pubmed/30713601
http://dx.doi.org/10.18632/oncotarget.26530
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