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

ABSTRACT: Abnormal FGFR1 alternative splicing is correlated with tumorigenicity and poor prognosis in several tumor types. We sought to determine the roles of FGFR1? and FGFR1? variants in breast cancer. TCGA samples and cell lines were analyzed for FGFR1?/FGFR1? 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? but not FGFR1? levels. FGFR1? expression levels and FGFR1?/FGFR1? ratio were higher in basal subtype samples than in ER-positive/luminal samples in both TCGA and breast cancer cell lines. Both FGFR1? and FGFR1? induced transformation of MCF-10A cells. However, only FGFR1?-expressing cells, not FGFR1?, enhanced cell growth and cell motility. Cells with higher FGFR1? levels and FGFR1?/FGFR1? ratio were more sensitive to FGFR inhibitor BGJ-398. Interestingly, in ER-negative cells, FGFR inhibitors decreased FGFR1? levels, likely by increasing expression of splicing repressor PTBP1. In ER-positive cells, estrogen treatment increased FGFR1? 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?/FGFR1? splicing plays an important role in breast cancer.

SUBMITTER: Zhao M 

PROVIDER: S-EPMC6343755 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature