title: An inducible knockout mouse to model the cell-autonomous role of PTEN in initiating endometrial, prostate and thyroid neoplasias.
abstract: PTEN is one of the most frequently mutated tumor suppressor genes in human cancers. The role of PTEN in carcinogenesis has been validated by knockout mouse models. PTEN heterozygous mice develop neoplasms in multiple organs. Unfortunately, the embryonic lethality of biallelic excision of PTEN has inhibited the study of complete PTEN deletion in the development and progression of cancer. By crossing PTEN conditional knockout mice with transgenic mice expressing a tamoxifen-inducible Cre-ER(T) under the control of a chicken actin promoter, we have generated a tamoxifen-inducible mouse model that allows temporal control of PTEN deletion. Interestingly, administration of a single dose of tamoxifen resulted in PTEN deletion mainly in epithelial cells, but not in stromal, mesenchymal or hematopoietic cells. Using the mT/mG double-fluorescent Cre reporter mice, we demonstrate that epithelial-specific PTEN excision was caused by differential Cre activity among tissues and cells types. Tamoxifen-induced deletion of PTEN resulted in extremely rapid and consistent formation of endometrial in situ adenocarcinoma, prostate intraepithelial neoplasia and thyroid hyperplasia. We also analyzed the role of PTEN ablation in other epithelial cells, such as the tubular cells of the kidney, hepatocytes, colonic epithelial cells or bronchiolar epithelium, but those tissues did not exhibit neoplastic growth. Finally, to validate this model as a tool to assay the efficacy of anti-tumor drugs in PTEN deficiency, we administered the mTOR inhibitor everolimus to mice with induced PTEN deletion. Everolimus dramatically reduced the progression of endometrial proliferations and significantly reduced thyroid hyperplasia. This model could be a valuable tool to study the cell-autonomous mechanisms involved in PTEN-loss-induced carcinogenesis and provides a good platform to study the effect of anti-neoplastic drugs on PTEN-negative tumors.
authors.affiliation: Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mirantes
authors.forename: Núria
authors.initials: N
authors.lastname: Eritja
authors.forename: Maria Alba
authors.initials: MA
authors.lastname: Dosil
authors.forename: Maria
authors.initials: M
authors.lastname: Santacana
authors.forename: Judit
authors.initials: J
authors.lastname: Pallares
authors.forename: Sónia
authors.initials: S
authors.lastname: Gatius
authors.forename: Laura
authors.initials: L
authors.lastname: Bergadà
authors.forename: Oscar
authors.initials: O
authors.lastname: Maiques
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.forename: Xavier
authors.initials: X
authors.lastname: Dolcet
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000483:Alleles; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000473:pathology*; D004717:Endometrium / Q000187:drug effects / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000068338:Everolimus; D005260:Female; D017353:Gene Deletion; D006801:Humans; D006965:Hyperplasia; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011230:Precancerous Conditions / Q000188:drug therapy / Q000473:pathology*; D019048:Prostatic Intraepithelial Neoplasia / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011995:Recombination, Genetic / Q000235:genetics; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013629:Tamoxifen / Q000494:pharmacology; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000473:pathology*
chemical_list: D013629:Tamoxifen; D000068338:Everolimus; C045073:Cre recombinase; D019426:Integrases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020123:Sirolimus