Abstract
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.
Highlights
Breast cancer has high incidence and mortality rate and remains the second leading cause of cancer death in women world-wide [1, 2]
We found that FGFR1α expression levels were significantly higher in FGFR1-amplified samples than that in non-amplified samples (Figure 1A)
FGFR1β expression did not exhibit a significant difference between the groups, its median level was slightly higher in FGFR1-amplified samples compared to nonamplified samples (-5.63 vs -7.56) (Figure 1A)
Summary
Breast cancer has high incidence and mortality rate and remains the second leading cause of cancer death in women world-wide [1, 2]. Alternative splicing events have been discovered in FGFR1 which www.oncotarget.com were implicated in genesis and development of malignant tumors, including breast cancer [6, 11, 12]. Alternative inclusion/exclusion of α-exon (exon 3) that covers the IgI and AB linker region creates two splicing forms, FGFR1α and FGFR1β respectively [15,16,17] (Supplementary Figure 1). This FGFR1 splicing event attracted attention during the past a couple of decades for their differential roles in cancer biology. Several studies have implicated that overexpression of FGFR1β is associated with tumorigenesis and poor survival in multiple tumors [15, 17,18,19], while
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