FOXA1 deletion in luminal epithelium causes prostatic hyperplasia and alteration of differentiated phenotype

• Published in: Laboratory investigation 2014-07, Vol.94 (7), p.726-739
• Main Authors: DeGraff, David J, Grabowska, Magdalena M, Case, Tom C, Yu, Xiuping, Herrick, Mary K, Hayward, William J, Strand, Douglas W, Cates, Justin M, Hayward, Simon W, Gao, Nan, Walter, Michael A, Buttyan, Ralph, Yi, Yajun, Kaestner, Klaus H, Matusik, Robert J
• Format: Article
• Language: English
• Subjects: 631/136; 631/337; 631/67/589/466; 692/698/1864/1752; Animals; Cell Differentiation - genetics; Epithelium - metabolism; Epithelium - pathology; Hepatocyte Nuclear Factor 3-alpha - deficiency; Hepatocyte Nuclear Factor 3-alpha - genetics; Hepatocyte Nuclear Factor 3-alpha - metabolism; Immunohistochemistry; Integrases - genetics; Integrases - metabolism; Laboratory Medicine; Male; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Mice, Transgenic; Microscopy, Fluorescence; Oligonucleotide Array Sequence Analysis; Pathology; Prostate - metabolism; Prostate - pathology; Prostatic Hyperplasia - genetics; Prostatic Hyperplasia - metabolism; research-article; Reverse Transcriptase Polymerase Chain Reaction; Seminal Vesicles - metabolism; Transcriptome - genetics
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2014.64

The forkhead box (Fox) superfamily of transcription factors has essential roles in organogenesis and tissue differentiation. Foxa1 and Foxa2 are expressed during prostate budding and ductal morphogenesis, whereas Foxa1 expression is retained in adult prostate epithelium. Previous characterization of prostatic tissue rescued from embryonic Foxa1 knockout mice revealed Foxa1 to be essential for ductal morphogenesis and epithelial maturation. However, it is unknown whether Foxa1 is required to maintain the differentiated status in adult prostate epithelium. Here, we employed the PBCre4 transgenic system and determined the impact of prostate-specific Foxa1 deletion in adult murine epithelium. PBCre4/Foxa1 loxp/loxp mouse prostates showed progressive florid hyperplasia with extensive cribriform patterning, with the anterior prostate being most affected. Immunohistochemistry studies show mosaic Foxa1 KO consistent with PBCre4 activity, with Foxa1 KO epithelial cells specifically exhibiting altered cell morphology, increased proliferation, and elevated expression of basal cell markers. Castration studies showed that, while PBCre4/Foxa1 loxp/loxp prostates did not exhibit altered sensitivity in response to hormone ablation compared with control prostates, the number of Foxa1-positive cells in mosaic Foxa1 KO prostates was significantly reduced compared with Foxa1-negative cells following castration. Unexpectedly, gene expression profile analyses revealed that Foxa1 deletion caused abnormal expression of seminal vesicle-associated genes in KO prostates. In summary, these results indicate Foxa1 expression is required for the maintenance of prostatic cellular differentiation.