Loss of FOXA1 Drives Sexually Dimorphic Changes in Urothelial Differentiation and Is an Independent Predictor of Poor Prognosis in Bladder Cancer

Opal L Reddy, Justin M Cates, Lan L Gellert, Henry S Crist, Zhaohai Yang, Hironobu Yamashita, John A Taylor, Joseph A Smith, Sam S Chang, Michael S Cookson, Chaochen You, Daniel A Barocas, Magdalena M Grabowska, Fei Ye, Xue-Ru Wu, Yajun Yi, Robert J Matusik, Klaus H Kaestner, Peter E Clark, David J DeGraff

Research output: Contribution to journalJournal articleResearchpeer-review


We previously found loss of forkhead box A1 (FOXA1) expression to be associated with aggressive urothelial carcinoma of the bladder, as well as increased tumor proliferation and invasion. These initial findings were substantiated by The Cancer Genome Atlas, which identified FOXA1 mutations in a subset of bladder cancers. However, the prognostic significance of FOXA1 inactivation and the effect of FOXA1 loss on urothelial differentiation remain unknown. Application of a univariate analysis (log-rank) and a multivariate Cox proportional hazards regression model revealed that loss of FOXA1 expression is an independent predictor of decreased overall survival. An ubiquitin Cre-driven system ablating Foxa1 expression in urothelium of adult mice resulted in sex-specific histologic alterations, with male mice developing urothelial hyperplasia and female mice developing keratinizing squamous metaplasia. Microarray analysis confirmed these findings and revealed a significant increase in cytokeratin 14 expression in the urothelium of the female Foxa1 knockout mouse and an increase in the expression of a number of genes normally associated with keratinocyte differentiation. IHC confirmed increased cytokeratin 14 expression in female bladders and additionally revealed enrichment of cytokeratin 14-positive basal cells in the hyperplastic urothelial mucosa in male Foxa1 knockout mice. Analysis of human tumor specimens confirmed a significant relationship between loss of FOXA1 and increased cytokeratin 14 expression.

Original languageEnglish
JournalThe American Journal of Pathology
Issue number5
Pages (from-to)1385-95
Publication statusPublished - 2015
Externally publishedYes


  • Aged
  • Animals
  • Biomarkers, Tumor
  • Carcinoma, Transitional Cell
  • Cell Differentiation
  • Disease Models, Animal
  • Female
  • Hepatocyte Nuclear Factor 3-alpha
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Keratin-14
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Prognosis
  • Proportional Hazards Models
  • Sex Characteristics
  • Tissue Array Analysis
  • Transcriptome
  • Urinary Bladder Neoplasms
  • Urothelium
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Fingerprint Dive into the research topics of 'Loss of FOXA1 Drives Sexually Dimorphic Changes in Urothelial Differentiation and Is an Independent Predictor of Poor Prognosis in Bladder Cancer'. Together they form a unique fingerprint.

Cite this