%0 Journal Article
%T FGFR1¦Â is a driver isoform of FGFR1 alternative splicing in breast cancer cells
%A Funda Meric-Bernstam
%A Ming Zhao
%A Ming-Lei Zhuo
%A Xiaofeng Zheng
%A Xiaoping Su
%J Archive of "Oncotarget".
%D 2019
%R 10.18632/oncotarget.26530
%X Abnormal FGFR1 alternative splicing is correlated with tumorigenicity and poor prognosis in several tumor types. We sought to determine the roles of FGFR1¦Á and FGFR1¦Â variants in breast cancer. TCGA samples and cell lines were analyzed for FGFR1¦Á/FGFR1¦Â 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 FGFR1¦Á but not FGFR1¦Â levels. FGFR1¦Â expression levels and FGFR1¦Â/FGFR1¦Á ratio were higher in basal subtype samples than in ER-positive/luminal samples in both TCGA and breast cancer cell lines. Both FGFR1¦Á and FGFR1¦Â induced transformation of MCF-10A cells. However, only FGFR1¦Â-expressing cells, not FGFR1¦Á, enhanced cell growth and cell motility. Cells with higher FGFR1¦Â levels and FGFR1¦Â/FGFR1¦Á ratio were more sensitive to FGFR inhibitor BGJ-398. Interestingly, in ER-negative cells, FGFR inhibitors decreased FGFR1¦Â levels, likely by increasing expression of splicing repressor PTBP1. In ER-positive cells, estrogen treatment increased FGFR1¦Â 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 FGFR1¦Á/FGFR1¦Â splicing plays an important role in breast cancer
%K FGFR1
%K alternative splicing
%K breast cancer
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343755/