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

Preety Bajwa, Sarah M. Nielsen, Janine Lombard, Loui Rassam, Pravin Nahar, Bo R. Rueda, John E. Wilkinson, Richard A. Miller, Pradeep S. Tanwar
In: Oncotarget · 2016 · vol. 8(5) , pp. 7265–7275 · doi:10.18632/oncotarget.13919 · PMID:27980219 · PMC5352319 · W2565961256
article OA: gold CC0 ⤵ 7 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-09 ⓘ

Overactive mTOR signaling in aged women and mice promotes endometrial hyperplasia, which rapamycin treatment can suppress.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-09 ⓘ

The paper investigated whether age-associated endometrial hyperplasia is driven by hyperactive mTOR signaling, using post-menopausal human endometrial tissue, cultured endometrial cells, and aged mouse models. In both humans and 18–20-month-old mice, the authors found increased phosphorylation of S6 (pS6; a marker of mTOR activation) specifically in hyperplastic epithelial glands, and TCGA analysis showed frequent genetic alterations across PI3K–mTOR pathway components in endometrial cancer. To test causality, they used Pten dysregulation models: Pten loss (Pten+/−) produced hyperplastic, disorganized endometrium with elevated pS6, whereas Pten overexpression (Ptentg) prevented hyperplastic changes and reduced pS6. As a limitation, the study relies on pS6 immunostaining and mouse modeling to infer pathway activity and does not fully establish upstream regulators or direct functional mechanisms beyond the observed associations, but it reports that pharmacologic mTOR inhibition with rapamycin reduced cystic hyperplasia in aged uteri at a high dose. This paper is centrally about endometriosis and/or adenomyosis — it links mTOR-driven endometrial hyperplasia to the gland invasion pattern described in adenomyosis and reports that aged mice show endometrial glands within the myometrium, a feature relevant to adenomyosis.

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Abstract

// Preety Bajwa 1 , Sarah Nielsen 2 , Janine M. Lombard 3,4 , Loui Rassam 2,3 , Pravin Nahar 3,5 , Bo R. Rueda 6 , J. Erby Wilkinson 7 , Richard A. Miller 8 and Pradeep S. Tanwar 1 1 Gynaecology Oncology Group, School of Biomedical Sciences and Pharmacy, Callaghan, New South Wales, Australia 2 Hunter Cancer Biobank, Callaghan, New South Wales, Australia 3 School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia 4 Department of Medical Oncology, Gynaecology Oncology, Calvary Mater Newcastle, Waratah, New South Wales, Australia 5 Gynaecology and Obstetrics, John Hunter Hospital, New Lambton, New South Wales, Australia 6 Vincent Department of Obstetrics and Gynecology and Department of Obstetrics & Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital and Gynecologic Oncology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 7 Department of Pathology, Unit for Laboratory Animal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA 8 Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA Correspondence to: Pradeep S. Tanwar, email: // Keywords : endometrial, mTOR, rapalogs, aging, PI3K, Pten, Gerotarget Received : October 11, 2016 Accepted : December 05, 2016 Published : December 12, 2016 Abstract 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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