Abstract P6-20-12: FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells

Abstract

Abstract Background: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. Methods: TCGA breast cancer samples and cell lines were analyzed for FGFR1α and FGFR1β expression. MCF-10A cells were used to overexpress these variants. Cell growth was assessed by SRB and colony formation assays. Cell transformation was assessed by 3D-Matrigel, soft agar, cell motility assays. Cell survival assay was used to determine drug IC50. Results: In the TCGA, compared to FGFR1 non-amplified samples, FGFR1-amplified samples had significantly higher FGFR1α, but not FGR1β levels. FGFR1β expression levels and FGFR1β/FGFR1α ratio were higher in basal subtype samples than in luminal samples in both the TCGA and in a panel of breast cancer cell lines. Both FGFR1α and FGFR1b induced transformation of MCF-10A cells. However, only FGFR1β-expressing cells, not FGFR1α, enhanced cell growth, cell motility, and FGFR signaling. Cells with higher FGFR1β levels and FGFR1β/FGFR1α ratio were more sensitive to FGFR inhibitor BGJ-398. Interestingly, in ER-negative cells, BGJ-398 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. Conclusions: These findings suggest that FGFR1 alternative splicing plays an important role in breast cancer, where FGFR1β functions as a driver isoform. Further work is needed to assess FGFR1β prognostic and predictive role. Citation Format: Zhao M, Zhuo M-L, Zheng X, Su X, Meric-Bernstam F. FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-12.