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Tumorigenesis requires accumulation of genetic and epigenetic alterations, some of which drive tumor initiation. “Oncogene addiction” describes the phenomenon that (1) well-established cancers are dependent on one mutated oncogene or pathway for the maintenance of a malignant phenotype and that (2) withdrawal of the single oncogenic event leads to growth arrest and/or cancer regression. While oncogene addiction has been experimentally validated in advanced tumor models, its role in tumor precursors has not been investigated. We utilized the requirement of Forkhead box A1 ( Foxa1 ) for transcriptional activation of the  Upk2- promoter to temporally control the expression of  Upk2-HRAS*  oncogene, an inducer of urothelial hyperplasia in transgenic mice. Inducible homozygous knockout of  Foxa1  in  Upk2-HRAS*/UBC-Cre   ERT2   /Foxa1   loxp/loxp   mice results in reduced HRAS* levels. This led to a marked reduction of urothelial proliferation as evidenced by urothelial thinning, degenerative changes such as intracellular vacuole formation, and reduced Ki67 expression. Reduced proliferation did not affect basal, Krt14-positive cells, supporting the fact that Foxa1-regulated  Upk2 - HRAS*  expression occurs primarily in supra-basal cells. Our results indicate that maintenance of urothelial hyperplasia in  Upk2-HRAS*  mice depends on continuous expression of Foxa1 and activated HRAS, and that mutated receptor tyrosine kinases, FOXA1 and/or other downstream effectors may mediate oncogene addiction in urothelial hyperplasia.

Maintenance of the bladder cancer precursor urothelial hyperplasia requires FOXA1 and persistent expression of oncogenic HRAS