17β-Estradiol sensitizes ovarian surface epithelium to transformation by suppressing Disabled-2 expression

Estrogen replacement therapy increases the risk of human ovarian cancer and exogenous estradiol accelerates the onset of ovarian cancer in mouse models. This study uses primary cultures of mouse ovarian surface epithelium (OSE) to demonstrate that one possible mechanism by which estrogen accelerates...

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Veröffentlicht in:Scientific reports Jg. 7; H. 1; S. 16702 - 12
Hauptverfasser: Vuong, Nhung H., Salah Salah, Omar, Vanderhyden, Barbara C.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 01.12.2017
Nature Publishing Group
Schlagworte:
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17β-Estradiol
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Adaptor Proteins, Signal Transducing
Adaptor Proteins, Vesicular Transport - biosynthesis
Adaptor Proteins, Vesicular Transport - genetics
Animal models
Animals
Apoptosis Regulatory Proteins
Carcinoma, Ovarian Epithelial - chemically induced
Carcinoma, Ovarian Epithelial - genetics
Carcinoma, Ovarian Epithelial - metabolism
Carcinoma, Ovarian Epithelial - pathology
Cell proliferation
Cell Transformation, Neoplastic - chemically induced
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Cell Transformation, Neoplastic - pathology
Contact inhibition
Dysplasia
Epithelial Cells - metabolism
Epithelial Cells - pathology
Epithelium
Epithelium - metabolism
Epithelium - pathology
Estradiol - adverse effects
Estradiol - pharmacology
Estrogen receptors
Estrogen replacement therapy
Estrogens
Female
Genetic transformation
Hormone replacement therapy
Humanities and Social Sciences
Humans
Mice
Mice, Knockout
miRNA
multidisciplinary
Ovarian cancer
Ovarian Neoplasms - chemically induced
Ovarian Neoplasms - genetics
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - pathology
Ovary - metabolism
Ovary - pathology
Science
Science (multidisciplinary)
Senescence
Tumor Suppressor Proteins - biosynthesis
Tumor Suppressor Proteins - genetics
Tumors
ISSN:2045-2322, 2045-2322
Online-Zugang:Volltext
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Zusammenfassung:Estrogen replacement therapy increases the risk of human ovarian cancer and exogenous estradiol accelerates the onset of ovarian cancer in mouse models. This study uses primary cultures of mouse ovarian surface epithelium (OSE) to demonstrate that one possible mechanism by which estrogen accelerates the initiation of ovarian cancer is by up-regulation of microRNA-378 via the ESR1 pathway to result in the down-regulation of a tumour suppressor called Disabled-2 ( Dab2 ). Estrogen suppression of Dab2 was reproducible in vivo and across many cell types including mouse oviductal epithelium and primary cultures of human ovarian cancer cells. Suppression of Dab2 resulted in increased proliferation, loss of contact inhibition, morphological dysplasia, and resistance to oncogene-induced senescence – all factors that can sensitize OSE to transformation. Given that DAB2 is highly expressed in healthy human OSE and is absent in the majority of ovarian tumours, this study has taken the first steps to provide a mechanistic explanation for how estrogen therapy may play a role in the initiation of ovarian cancer.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-16219-2