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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

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FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells.

Zhao Ming M Zhuo Ming-Lei ML Zheng Xiaofeng X Su Xiaoping X Meric-Bernstam Funda F

Oncotarget 20190101 1

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-amplif ...[more]

PMID: 30713601

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Project description:Estrogens play an important role in breast cancer (BC) development and progression; when the two isoforms of the estrogen receptor (ER? and ER?) are co-expressed each of them mediate specific effects of these hormones in BC cells. ER? has been suggested to exert an antagonist role toward the oncogenic activities of ER?, and for this reason it is considered an oncosuppressor. As clinical evidence regarding a prognostic role for this receptor subtype in hormone-responsive BC is still limited and conflicting, more knowledge is required on the biological functions of ER? in cancer cells. We have previously described the ER? and ER? interactomes from BC cells, identifying specific and distinct patterns of protein interactions for the two receptors. In particular, we identified factors involved in mRNA splicing and maturation as important components of both ER? and ER? pathways. Guided by these findings, here we performed RNA sequencing to investigate in depth the differences in the early transcriptional events and RNA splicing patterns induced by estradiol in cells expressing ER? alone or ER? and ER?.Exon skipping was the most abundant splicing event in the post-transcriptional regulation by estradiol. We identified several splicing events induced by ER? alone and by ER?+ER?, demonstrating for the first time that ER? significantly affects estrogen-induced splicing in BC cells, as revealed by modification of a subset of ER?-dependent splicing by ER?, as well as by the presence of splicing isoforms only in ER?+cells. In particular, we observed that ER?+BC cell lines exhibited around 2-fold more splicing events than the ER?- cells. Interestingly, we identified putative direct targets of ER?-mediated alternative splicing by correlating the genomic locations of ER? and ER? binding sites with estradiol-induced differential splicing in the corresponding genes.Taken together, these results demonstrate that ER? significantly affects estrogen-induced early transcription and mRNA splicing in hormone-responsive BC cells, providing novel information on the biological role of ER? in these tumors.

Dataset Information

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

Publications

FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells.

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