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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Vydáno v:	Scientific reports Ročník 7; číslo 1; s. 16702 - 12
Hlavní autoři:	Vuong, Nhung H., Salah Salah, Omar, Vanderhyden, Barbara C.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 01.12.2017 Nature Publishing Group
Témata:	13 13/106 13/51 14/19 14/63 17β-Estradiol 38 38/109 38/61 631/443/494/2732/2730 631/67/1517/1709 631/80/304 64 64/60 82/1 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
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-017-16219-2