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Title:
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An inducible knockout mouse to model the cellautonomous role of PTEN in initiating endometrial, prostate and thyroid neoplasias
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Author:
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Mirantes Barbeito, Cristina; Eritja Sánchez, Núria; Dosil, Maria Alba; Santacana Espasa, Maria; Pallares, Judit; Gatius Calderó, Sònia; Bergadà Bertran, Laura; Maiques Carlos, Oscar; Matias-Guiu, Xavier; Dolcet Roca, Xavier
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Notes:
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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-ERT under the control of a chicken actin promoter, we have generated a tamoxifeninducible
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. |
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Rights:
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cc-by-nc-sa, (c) Company of Biologists, 2013
http://creativecommons.org/licenses/by-nc-sa/3.0/es/
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Document type:
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article
publishedVersion |
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Published by:
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Company of Biologists
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Share:
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