title: Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma.
abstract: Studies of prostate cancer pathogenesis and development of new therapies have been hampered by a lack of appropriate mouse models. We have generated PSA-Cre-ER(T2) mice that express the tamoxifen-dependent Cre-ER(T2) recombinase selectively in prostatic epithelium, thus allowing us to target floxed genes selectively in epithelial cells of fully differentiated prostate of adult mice and to modulate the number of genetically altered cells. Our present mouse model, in which prostate carcinogenesis is initiated through Cre-ER(T2)-mediated somatic biallelic ablation of the tumor suppressor gene PTEN after puberty, closely mimics the course of human cancer formation. Indeed, mutant mice developed prostate epithelium hyperplasia within 4 weeks after PTEN ablation and prostatic intraepithelial neoplasia (PIN) in all lobes within 2-3 months, with the highest incidence in the dorsolateral lobe, which is considered to be the most similar to the peripheral zone of the human prostate, in which adenocarcinoma is preferentially localized. Eight to 10 months after PTEN ablation some PINs of the dorsolateral lobe had progressed to adenocarcinoma, but no distant metastases were found up to 20 months after PTEN ablation, indicating that progression to metastasis requires an additional mutation or mutations. Interestingly, monoallelic Cre-ER(T2)-mediated PTEN ablation in epithelial cells of adult prostate also generated focal hyperplasia and PINs, but exclusively in the dorsolateral lobe, and in much lower number and after a longer latency. However, no progression to adenocarcinoma was observed. Because PTEN expression was undetectable in epithelial cells from these PINs, loss of PTEN function appears to act as a permissive event for uncontrolled cell proliferation.
authors.affiliation: Department of Functional Genomics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, F-67400 Illkirch, France.
authors.forename: Chandrahas Koumar
authors.initials: CK
authors.lastname: Ratnacaram
authors.forename: Marius
authors.initials: M
authors.lastname: Teletin
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Meng
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000375:Aging / Q000502:physiology*; D000483:Alleles; D000818:Animals; D048430:Cell Shape; D004195:Disease Models, Animal; D004848:Epithelium / Q000378:metabolism; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse