Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Müllerian duct epithelium

Laronda, Monica M., Unno, Kenji, Ishi, Kazutomo, Serna, Vanida A., Butler, Lindsey M., Mills, Alea A., Orvis, Grant D., Behringer, Richard R., Deng, Chuxia, Sinha, Satrajit, Kurita, Takeshi (July 2013) Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Müllerian duct epithelium. Developmental Biology, 381 (1). pp. 5-16. ISSN 0012-1606

Abstract

Abstract Women exposed to diethylstilbestrol (DES) in utero frequently develop vaginal adenosis, from which clear cell adenocarcinoma can arise. Despite decades of extensive investigation, the molecular pathogenesis of DES-associated vaginal adenosis remains elusive. Here we report that DES induces vaginal adenosis by inhibiting the BMP4/Activin A-regulated vaginal cell fate decision through a downregulation of RUNX1. BMP4 and Activin A produced by vaginal mesenchyme synergistically activated the expression of ΔNp63, thus deciding vaginal epithelial cell fate in the Müllerian duct epithelial cells (MDECs) via direct binding of SMADs on the highly conserved 5′ sequence of ΔNp63. Therefore, mice in which Smad4 was deleted in MDECs failed to express ΔNp63 in vaginal epithelium and developed adenosis. This SMAD-dependent ΔNp63 activation required RUNX1, a binding partner of SMADs. Conditional deletion of Runx1 in the MDECs induced adenosis in the cranial portion of vagina, which mimicked the effect of developmental DES-exposure. Furthermore, neonatal DES exposure downregulated RUNX1 in the fornix of the vagina, where DES-associated adenosis is frequently found. This observation strongly suggests that the downregulation of RUNX1 is the cause of vaginal adenosis. However, once cell fate was determined, the BMP/Activin-SMAD/RUNX1 signaling pathway became dispensable for the maintenance of ΔNp63 expression in vaginal epithelium. Instead, the activity of the ΔNp63 locus in vaginal epithelium was maintained by a ΔNp63–dependent mechanism. This is the first demonstration of a molecular mechanism through which developmental chemical exposure causes precancerous lesions by altering cell fate.

Item Type:	Paper
Uncontrolled Keywords:	DES daughter Vaginal clear cell adenocarcinoma Endocrine disruptor p63
Subjects:	diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p63
CSHL Authors:	Mills, Alea A.
Communities:	CSHL Cancer Center Program > Cancer Genetics CSHL Cancer Center Shared Resources > Animal Services CSHL Cancer Center Shared Resources > Gene Targeting Service CSHL labs > Mills lab CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service
Depositing User:	Matt Covey
Date:	3 July 2013
Date Deposited:	19 Jul 2013 14:23
Last Modified:	02 Feb 2017 16:19
PMCID:	PMC3947918
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/28455

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