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 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 Degraff

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Article number1980
Pages (from-to)1385-1395
Number of pages11
JournalAmerican Journal of Pathology
Volume185
Issue number5
DOIs
StatePublished - May 1 2015

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Keratin-14
Urinary Bladder Neoplasms
Urothelium
Knockout Mice
Urinary Bladder
Neoplasms
Atlases
Metaplasia
Microarray Analysis
Ubiquitin
Keratinocytes
Proportional Hazards Models
Hyperplasia
Mucous Membrane
Genome
Carcinoma
Mutation
Survival
Genes

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Reddy, Opal L. ; Cates, Justin M. ; Gellert, Lan L. ; Crist, Henry ; Yang, Zhaohai ; Yamashita, Hironobu ; Taylor, John A. ; Smith, Joseph A. ; Chang, Sam S. ; Cookson, Michael S. ; You, Chaochen ; Barocas, Daniel A. ; Grabowska, Magdalena M. ; Ye, Fei ; Wu, Xue Ru ; Yi, Yajun ; Matusik, Robert J. ; Kaestner, Klaus H. ; Clark, Peter E. ; Degraff, David. / Loss of FOXA1 drives sexually dimorphic changes in urothelial differentiation and is an independent predictor of poor prognosis in bladder cancer. In: American Journal of Pathology. 2015 ; Vol. 185, No. 5. pp. 1385-1395.
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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.",
author = "Reddy, {Opal L.} and Cates, {Justin M.} and Gellert, {Lan L.} and Henry Crist and Zhaohai Yang and Hironobu Yamashita and Taylor, {John A.} and Smith, {Joseph A.} and Chang, {Sam S.} and Cookson, {Michael S.} and Chaochen You and Barocas, {Daniel A.} and Grabowska, {Magdalena M.} and Fei Ye and Wu, {Xue Ru} and Yajun Yi and Matusik, {Robert J.} and Kaestner, {Klaus H.} and Clark, {Peter E.} and David Degraff",
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Reddy, OL, Cates, JM, Gellert, LL, Crist, H, Yang, Z, Yamashita, H, Taylor, JA, Smith, JA, Chang, SS, Cookson, MS, You, C, Barocas, DA, Grabowska, MM, Ye, F, Wu, XR, Yi, Y, Matusik, RJ, Kaestner, KH, Clark, PE & Degraff, D 2015, 'Loss of FOXA1 drives sexually dimorphic changes in urothelial differentiation and is an independent predictor of poor prognosis in bladder cancer', American Journal of Pathology, vol. 185, no. 5, 1980, pp. 1385-1395. https://doi.org/10.1016/j.ajpath.2015.01.014

Loss of FOXA1 drives sexually dimorphic changes in urothelial differentiation and is an independent predictor of poor prognosis in bladder cancer. / Reddy, Opal L.; Cates, Justin M.; Gellert, Lan L.; Crist, Henry; Yang, Zhaohai; Yamashita, Hironobu; Taylor, John A.; Smith, Joseph A.; Chang, Sam S.; Cookson, Michael S.; You, Chaochen; Barocas, Daniel A.; Grabowska, Magdalena M.; Ye, Fei; Wu, Xue Ru; Yi, Yajun; Matusik, Robert J.; Kaestner, Klaus H.; Clark, Peter E.; Degraff, David.

In: American Journal of Pathology, Vol. 185, No. 5, 1980, 01.05.2015, p. 1385-1395.

Research output: Contribution to journalArticle

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T1 - Loss of FOXA1 drives sexually dimorphic changes in urothelial differentiation and is an independent predictor of poor prognosis in bladder cancer

AU - Reddy, Opal L.

AU - Cates, Justin M.

AU - Gellert, Lan L.

AU - Crist, Henry

AU - Yang, Zhaohai

AU - Yamashita, Hironobu

AU - Taylor, John A.

AU - Smith, Joseph A.

AU - Chang, Sam S.

AU - Cookson, Michael S.

AU - You, Chaochen

AU - Barocas, Daniel A.

AU - Grabowska, Magdalena M.

AU - Ye, Fei

AU - Wu, Xue Ru

AU - Yi, Yajun

AU - Matusik, Robert J.

AU - Kaestner, Klaus H.

AU - Clark, Peter E.

AU - Degraff, David

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