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Mol Cancer Res. 2019 Oct;17(10):2115-2125. doi: 10.1158/1541-7786.MCR-19-0415. Epub 2019 Jul 2.

A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance.

Author information

1
Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, GW Cancer Center, Washington, D. C.
2
Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, Princess Anne, Maryland.
3
Cancer Epidemiology Program, University of Hawaii, Honolulu, Hawaii.
4
Department of Computational Medicine and Bioinformatics, School of Medicine, University of Michigan, Ann Arbor, Michigan.
5
Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.
6
Department of Pathology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
7
Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of Health Sciences, Bethesda, Maryland.
8
Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, GW Cancer Center, Washington, D. C. nhlee@gwu.edu.

Abstract

Alternative splicing (AS) has been shown to participate in prostate cancer development and progression; however, a link between AS and prostate cancer health disparities has been largely unexplored. Here we report on the cloning of a novel splice variant of FGFR3 that is preferentially expressed in African American (AA) prostate cancer. This novel variant (FGFR3-S) omits exon 14, comprising 123 nucleotides that encode the activation loop in the intracellular split kinase domain. Ectopic overexpression of FGFR3-S in European American (EA) prostate cancer cell lines (PC-3 and LNCaP) led to enhanced receptor autophosphorylation and increased activation of the downstream signaling effectors AKT, STAT3, and ribosomal S6 compared with FGFR3-L (retains exon 14). The increased oncogenic signaling imparted by FGFR3-S was associated with a substantial gain in proliferative and antiapoptotic activities, as well as a modest but significant gain in cell motility. Moreover, the FGFR3-S-conferred proliferative and motility gains were highly resistant to the pan-FGFR small-molecule inhibitor dovitinib and the antiapoptotic gain was insensitive to the cytotoxic drug docetaxel, which stands in marked contrast with dovitinib- and docetaxel-sensitive FGFR3-L. In an in vivo xenograft model, mice injected with PC-3 cells overexpressing FGFR3-S exhibited significantly increased tumor growth and resistance to dovitinib treatment compared with cells overexpressing FGFR3-L. In agreement with our in vitro and in vivo findings, a high FGFR3-S/FGFR3-L expression ratio in prostate cancer specimens was associated with poor patient prognosis. IMPLICATIONS: This work identifies a novel FGFR3 splice variant and supports the hypothesis that differential AS participates in prostate cancer health disparities.

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