Journal
CLINICAL CANCER RESEARCH
Volume 18, Issue 14, Pages 3780-3790Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-10-3063
Keywords
-
Categories
Funding
- NIH [K12 HD043494, R01 CA122706, T32 CA059365]
- Alex's Lemonade Stand Foundation
- Duke Children's Miracle Network
Ask authors/readers for more resources
Purpose: Rhabdomyosarcoma (RMS) is a malignancy with features of skeletal muscle, and the most common soft tissue sarcoma of childhood. Survival for high-risk groups is approximately 30% at 5 years and there are no durable therapies tailored to its genetic aberrations. During genetic modeling of the common RMS variants, embryonal RMS (eRMS) and alveolar RMS (aRMS), we noted that the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 4 (FGFR4) was upregulated as an early event in aRMS. Herein, we evaluated the expression of FGFR4 in eRMS compared with aRMS, and whether FGFR4 had similar or distinct roles in their tumorigenesis. Experimental Design: Human RMS cell lines and tumor tissue were analyzed for FGFR4 expression by immunoblot and immunohistochemistry. Genetic and pharmacologic loss-of-function of FGFR4 using virally transduced short hairpin RNA (shRNA) and the FGFR small-molecule inhibitor PD173074, respectively, were used to study the role of FGFR4 in RMS cell lines in vitro and xenografts in vivo. Expression of the antiapoptotic protein BCL2L1 was also examined. Results: FGFR4 is expressed in both RMS subtypes, but protein expression is higher in aRMS. The signature aRMS gene fusion product, PAX3-FOXO1, induced FGFR4 expression in primary human myoblasts. In eRMS, FGFR4 loss-of-function reduced cell proliferation in vitro and xenograft formation in vivo. In aRMS, it diminished cell survival in vitro. In myoblasts and aRMS, FGFR4 was necessary and sufficient for expression of BCL2L1 whereas in eRMS, this induction was not observed, suggesting differential FGFR4 signaling. Conclusion: These studies define dichotomous roles for FGFR4 in RMS subtypes, and support further study of FGFR4 as a therapeutic target. Clin Cancer Res; 18(14); 3780-90. (C)2012 AACR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available