title: Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Müllerian duct epithelium.
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.
authors.affiliation: Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Laronda
authors.forename: Kenji
authors.initials: K
authors.lastname: Unno
authors.forename: Kazutomo
authors.initials: K
authors.lastname: Ishi
authors.forename: Vanida A
authors.initials: VA
authors.lastname: Serna
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: Butler
authors.forename: Alea A
authors.initials: AA
authors.lastname: Mills
authors.forename: Grant D
authors.initials: GD
authors.lastname: Orvis
authors.forename: Richard R
authors.initials: RR
authors.lastname: Behringer
authors.forename: Chuxia
authors.initials: C
authors.lastname: Deng
authors.forename: Satrajit
authors.initials: S
authors.lastname: Sinha
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kurita
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D019070:Cell Lineage; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D003433:Crosses, Genetic; D004054:Diethylstilbestrol / Q000009:adverse effects*; D004848:Epithelium / Q000187:drug effects*; D004968:Estrogens, Non-Steroidal / Q000009:adverse effects; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009095:Mullerian Ducts / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D051785:Smad Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014599:Uterus / Q000196:embryology; D014621:Vagina / Q000187:drug effects / Q000196:embryology*; D014623:Vaginal Diseases / Q000139:chemically induced
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004968:Estrogens, Non-Steroidal; D010750:Phosphoproteins; C493726:Runx1 protein, mouse; D051785:Smad Proteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C422405:activin A; D028341:Activins; D004054:Diethylstilbestrol
keywords: DES daughter; Endocrine disruptor; Vaginal clear cell adenocarcinoma; p63