Biased Expression of the FOXP3 Delta 3 Isoform in Aggressive Bladder Cancer Mediates Differentiation and Cisplatin Chemotherapy Resistance

• Published in: Clinical cancer research Vol. 22; no. 21; pp. 5349 - 5361
• Main Authors: Zhang, Hanwei, Prado, Kris, Zhang, Kelvin X, Peek, Elizabeth M, Lee, Jane, Wang, Xiaoyan, Huang, Jiaoti, Li, Gang, Pellegrini, Matteo, Chin, Arnold I
• Format: Journal Article
• Language: English
• Published: 01.11.2016
• ISSN: 1078-0432
• DOI: 10.1158/1078-0432.CCR-15-2581

Purpose: The transcriptional regulation mediating cancer cell differentiation into distinct molecular subtypes and modulating sensitivity to existing treatments is an enticing therapeutic target. Our objective was to characterize the ability of the forkhead/winged transcription factor FOXP3 to modulate the differentiation of bladder cancer.Experimental Design: Expression of FOXP3 was analyzed by immunohistochemistry in a tumor microarray of 587 samples and overall survival in a subset of 187 patients following radical cystectomy. Functional assays were performed in SW780 and HT1376 cell lines in vitro and in vivo and gene expression profiling performed by RNA-Seq. Validation was undertaken using gene expression profiles of 131 patients from The Cancer Genome Atlas (TCGA) consortium in bladder cancer.Results: FOXP3 expression correlates with bladder cancer stage and inversely with overall survival, with biased expression of the FOXP3 Delta 3 isoform. Functional assays of FOXP3 Delta 3 demonstrated resistance to chemotherapy in vitro, whereas subcutaneous xenografts overexpressing FOXP3 Delta 3 developed larger and more poorly differentiated bladder cancers. RNA expression profiling revealed a unique FOXP3 Delta 3 gene signature supporting a role in chemotherapy resistance. Accordingly, knockdown of Foxp3 by siRNA in HT1376 cells conferred sensitivity to cisplatin- and gemcitabine-induced cytotoxicity. Validation in TCGA dataset demonstrated increased expression of FOXP3 in subtypes II to IV and skewing of molecular subtypes based on FOXP3 Delta 3-specific gene expression.Conclusions: (i) Biased expression of the FOXP3 Delta 3 isoform in bladder cancer inversely correlates with overall survival, (ii) FOXP3 Delta 3 induces a unique gene program that mediates cancer differentiation, and (iii) FOXP3 Delta 3 may augment chemotherapy resistance. Clin Cancer Res; 22(21); 5349-61. copyright 2016 AACR.