Bladder cancer affects men more frequently than women and comprises molecular subtypes whose distribution differs by sex. Among the most frequent genetic alterations in this disease are activating mutations of fibroblast growth factor receptor 3 (FGFR3), which are particularly enriched in luminal papillary subtypes, whether in muscle-invasive or non-muscle-invasive tumors. It remained to be determined whether these mutations are capable of initiating bladder carcinogenesis on their own and whether they contribute to the sex bias observed among patients.
To address these questions, the authors developed a transgenic mouse model expressing the most frequent FGFR3 mutation, FGFR3-S249C, in urothelial cells. Bladder tumorigenesis was monitored in these animals, with or without exposure to a carcinogen (N-butyl-N-(4-hydroxybutyl)-nitrosamine, or BBN). Murine and human transcriptomic data were compared, and the activity of androgen receptors (AR) and estrogen receptors (ESR1) was assessed through the expression of their target genes and reporter assays, complemented by FGFR3 knockdown experiments in cell lines.
Expression of FGFR3-S249C is sufficient to induce low-grade papillary tumors in mice that recapitulate their human luminal counterpart at the histological, genomic, and transcriptomic levels; it also promotes the formation of BBN-induced basal tumors. The expression level of the transgene determines tumor incidence, and human FGFR3-mutated tumors are restricted to epithelia that naturally exhibit high receptor expression—an observation that could explain the absence of mutation-related tumors in breast or lung tissue, where normal FGFR3 expression is low, even though the S249C mutation is rarely selected there. The male bias, recapitulated in the mouse model, proves even more pronounced in human mutated tumors than in wild-type tumors, and is associated with higher AR activity and lower ESR1 activity. Expression of mutated FGFR3 inhibits both ESR1 and AR activity in murine tumors and human cell lines, but only the causal link between FGFR3 activation and decreased ESR1 activity is demonstrated in tumors.
This model constitutes the first immunocompetent system of low-grade luminal papillary carcinoma induced by mutated FGFR3, with a tumor microenvironment closely resembling its human counterpart. The authors conclude that FGFR3 mutations initiate the formation of luminal papillary bladder tumors and promote the male sex bias, possibly through repression of ESR1 activity. These findings suggest a potential benefit of FGFR3 inhibitors at early stages and in premalignant lesions, and indicate that the level of FGFR3 expression in a given tissue determines the tissue specificity of the carcinomas it generates.