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Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice

During aging, uncontrolled epithelial cell proliferation in the uterus results in endometrial hyperplasia and/or cancer development. The mTOR signaling pathway is one of the major regulators of aging as suppression of this pathway prolongs lifespan in model organisms. Genetic alterations in this pat...

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Autores principales: Bajwa, Preety, Nielsen, Sarah, Lombard, Janine M., Rassam, Loui, Nahar, Pravin, Rueda, Bo R., Wilkinson, J. Erby, Miller, Richard A., Tanwar, Pradeep S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352319/
https://www.ncbi.nlm.nih.gov/pubmed/27980219
http://dx.doi.org/10.18632/oncotarget.13919
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author Bajwa, Preety
Nielsen, Sarah
Lombard, Janine M.
Rassam, Loui
Nahar, Pravin
Rueda, Bo R.
Wilkinson, J. Erby
Miller, Richard A.
Tanwar, Pradeep S
author_facet Bajwa, Preety
Nielsen, Sarah
Lombard, Janine M.
Rassam, Loui
Nahar, Pravin
Rueda, Bo R.
Wilkinson, J. Erby
Miller, Richard A.
Tanwar, Pradeep S
author_sort Bajwa, Preety
collection PubMed
description During aging, uncontrolled epithelial cell proliferation in the uterus results in endometrial hyperplasia and/or cancer development. The mTOR signaling pathway is one of the major regulators of aging as suppression of this pathway prolongs lifespan in model organisms. Genetic alterations in this pathway via mutations and/or amplifications are often encountered in endometrial cancers. However, the exact contribution of mTOR signaling and uterine aging to endometrial pathologies is currently unclear. This study examined the role of mTOR signaling in uterine aging and its implications in the development of endometrial hyperplasia. The hyperplastic endometrium of both postmenopausal women and aged mice exhibited elevated mTOR activity as seen with increased expression of the pS6 protein. Analysis of uteri from Pten heterozygous and Pten overexpressing mice further confirmed that over-activation of mTOR signaling leads to endometrial hyperplasia. Pharmacological inhibition of mTOR signaling using rapamycin treatment suppressed endometrial hyperplasia in aged mice. Furthermore, treatment with mTOR inhibitors reduced colony size and proliferation of a PTEN negative endometrial cancer cell line in 3D culture. Collectively, this study suggests that hyperactivation of the mTOR pathway is involved in the development of endometrial hyperplasia in aged women and mice.
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spelling pubmed-53523192017-04-14 Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice Bajwa, Preety Nielsen, Sarah Lombard, Janine M. Rassam, Loui Nahar, Pravin Rueda, Bo R. Wilkinson, J. Erby Miller, Richard A. Tanwar, Pradeep S Oncotarget Priority Research Paper: Gerotarget During aging, uncontrolled epithelial cell proliferation in the uterus results in endometrial hyperplasia and/or cancer development. The mTOR signaling pathway is one of the major regulators of aging as suppression of this pathway prolongs lifespan in model organisms. Genetic alterations in this pathway via mutations and/or amplifications are often encountered in endometrial cancers. However, the exact contribution of mTOR signaling and uterine aging to endometrial pathologies is currently unclear. This study examined the role of mTOR signaling in uterine aging and its implications in the development of endometrial hyperplasia. The hyperplastic endometrium of both postmenopausal women and aged mice exhibited elevated mTOR activity as seen with increased expression of the pS6 protein. Analysis of uteri from Pten heterozygous and Pten overexpressing mice further confirmed that over-activation of mTOR signaling leads to endometrial hyperplasia. Pharmacological inhibition of mTOR signaling using rapamycin treatment suppressed endometrial hyperplasia in aged mice. Furthermore, treatment with mTOR inhibitors reduced colony size and proliferation of a PTEN negative endometrial cancer cell line in 3D culture. Collectively, this study suggests that hyperactivation of the mTOR pathway is involved in the development of endometrial hyperplasia in aged women and mice. Impact Journals LLC 2016-12-12 /pmc/articles/PMC5352319/ /pubmed/27980219 http://dx.doi.org/10.18632/oncotarget.13919 Text en Copyright: © 2017 Bajwa et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Priority Research Paper: Gerotarget
Bajwa, Preety
Nielsen, Sarah
Lombard, Janine M.
Rassam, Loui
Nahar, Pravin
Rueda, Bo R.
Wilkinson, J. Erby
Miller, Richard A.
Tanwar, Pradeep S
Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice
title Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice
title_full Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice
title_fullStr Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice
title_full_unstemmed Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice
title_short Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice
title_sort overactive mtor signaling leads to endometrial hyperplasia in aged women and mice
topic Priority Research Paper: Gerotarget
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352319/
https://www.ncbi.nlm.nih.gov/pubmed/27980219
http://dx.doi.org/10.18632/oncotarget.13919
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