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 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.
Competing Interests: CONFLICTS OF INTEREST Drs. Ming Zhao, Ming-Lei Zhuo, Xiaofeng Zheng, and Xiaoping Su have nothing to disclose. Dr. Meric-Bernstam reports grants from Novartis, AstraZeneca, Calithera, Bayer, Jounce, CytoMx, eFFECTOR, Zymeworks, PUMA Biotechnology, Curis, Millennium, Daiichi Sankyo, Abbvie, Guardant Health, and Takeda; grants and travel related fees from Taiho, Genentech, Debiopharm Group, and Pfizer; and served as a consultant to Inflection Biosciences, Pieris, Darwin Health, GRAIL, Clearlight Diagnostics, Dialectica, Sumitomo Dainippon, Spectrum, Samsung Bioepis, Aduro, OrigiMed, Xencor, Jackson Laboratory, and Mersana.