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An inducible knock-out mouse to model cell-autonomous role of PTEN in initiating endometrial, prostate and thyroid neoplasias.
Dis Model Mech. 2013 Feb 8;
Authors: Mirantes C, Eritja N, Dosil MA, Santacana M, Pallares J, Gatius S, Bergad� L, Maiques O, Matias-Guiu X, Dolcet X
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 knock-out mouse models. PTEN heterozygous mice develop neoplasms in multiple organs. Unfortunately, the embryonic lethality of biallelic excision of PTEN has conditioned the study of complete PTEN deletion in the development and progression of cancer. By crossing PTEN conditional mice with transgenic mice expressing a tamoxifen-inducible CRE:ER 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-tumoral drugs in PTEN-deficient, 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 may 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.
PMID: 23471917 [PubMed - as supplied by publisher]
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