title: Loss of FOXA1 Drives Sexually Dimorphic Changes in Urothelial Differentiation and Is an Independent Predictor of Poor Prognosis in Bladder Cancer.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California.
authors.forename: Opal L
authors.initials: OL
authors.lastname: Reddy
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Cates
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Lan L
authors.initials: LL
authors.lastname: Gellert
authors.affiliation: Department of Pathology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Henry S
authors.initials: HS
authors.lastname: Crist
authors.affiliation: Department of Pathology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Zhaohai
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pathology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yamashita
authors.affiliation: Division of Urology, University of Connecticut Health Center, Farmington, Connecticut.
authors.forename: John A
authors.initials: JA
authors.lastname: Taylor
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Sam S
authors.initials: SS
authors.lastname: Chang
authors.affiliation: Department of Urology, University of Oklahoma, Oklahoma City, Oklahoma.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Cookson
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Chaochen
authors.initials: C
authors.lastname: You
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Barocas
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Grabowska
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Departments of Urology and Pathology, New York University School of Medicine and Veterans Affairs Medical Center in Manhattan, New York, New York.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.affiliation: Institute for Integrative Genomics and Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Yi
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Matusik
authors.affiliation: Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Clark
authors.affiliation: Department of Pathology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania; Cancer Institute, Milton S. Hershey Medical Center, Hershey, Pennsylvania; Division of Urology, Department of Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Electronic address: ddegraff@hmc.psu.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: DeGraff
mesh_terms: D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002295:Carcinoma, Transitional Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D053547:Keratin-14; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D012727:Sex Characteristics; D046888:Tissue Array Analysis; D059467:Transcriptome; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D019459:Urothelium / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D053547:Keratin-14