title: The pace of prostatic intraepithelial neoplasia development is determined by the timing of Pten tumor suppressor gene excision.
abstract: Loss of the PTEN tumor suppressor is a common occurrence in human prostate cancer, particularly in advanced disease. In keeping with its role as a pivotal upstream regulator of the phosphatidylinositol 3-kinase signaling pathway, experimentally-induced deletion of Pten in the murine prostate invariably results in neoplasia. However, and unlike humans where prostate tumorigenesis likely evolves over decades, disease progression in the constitutively Pten deficient mouse prostate is relatively rapid, culminating in invasive cancer within several weeks post-puberty. Given that the prostate undergoes rapid androgen-dependent growth at puberty, and that Pten excisions during this time might be especially tumorigenic, we hypothesized that delaying prostate-specific Pten deletions until immediately after puberty might alter the pace of tumorigenesis. To this end we generated mice with a tamoxifen-inducible Cre recombinase transgene enabling temporal control over prostate-specific gene alterations. This line was then interbred with mice carrying floxed Pten alleles. Despite evidence of increased Akt/mTOR/S6K axis activity at early time points in Pten-deficient epithelial cells, excisions induced in the post-pubertal (6 wk-old) prostate yielded gradual acquisition of a range of lesions. These progressed from pre-malignant changes (nuclear atypia, focal hyperplasia) and low grade prostatic intraepithelial neoplasia (PIN) at 16-20 wks post-tamoxifen exposure, to overtly malignant lesions by approximately 1 yr of age, characterized by high-grade PIN and microinvasive carcinoma. In contrast, when Pten excisions were triggered in the pre-pubertal (2 week-old) prostate, neoplasia evolved over a more abbreviated time-frame, with a spectrum of premalignant lesions, as well as overt PIN and microinvasive carcinoma by 10-12 wks post-tamoxifen exposure. These results indicate that the developmental stage at which Pten deletions are induced dictates the pace of PIN development.
authors.affiliation: Department of Biochemistry and Molecular Biology, and The McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.
authors.forename: H Artee
authors.initials: HA
authors.lastname: Luchman
authors.forename: Hallgrimur
authors.initials: H
authors.lastname: Benediktsson
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Villemaire
authors.forename: Alan C
authors.initials: AC
authors.lastname: Peterson
authors.forename: Frank R
authors.initials: FR
authors.lastname: Jirik
mesh_terms: D000727:Androgen-Binding Protein / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D019390:Arrestins / Q000378:metabolism; D049109:Cell Proliferation; D003433:Crosses, Genetic; D018450:Disease Progression; D004848:Epithelium / Q000201:enzymology / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011230:Precancerous Conditions / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051381:Rats; D038601:Ribosomal Protein S6 / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000627:therapeutic use; D013997:Time Factors; D015854:Up-Regulation; D000071557:beta-Arrestins
chemical_list: D000727:Androgen-Binding Protein; D019390:Arrestins; D038601:Ribosomal Protein S6; D000071557:beta-Arrestins; D013629:Tamoxifen; C016601:afimoxifene; D019869:Phosphatidylinositol 3-Kinases; C045073:Cre recombinase; D019426:Integrases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse