Abstract
Women exposed to diethylstilbestrol (DES) in utero develop abnormalities, including cervicovaginal adenosis that can lead to cancer. We report that transient disruption of developmental signals by DES permanently changes expression of p63, thereby altering the developmental fate of Müllerian duct epithelium. The cell fate of Müllerian epithelium to be columnar (uterine) or squamous (cervicovaginal) is determined by mesenchymal induction during the perinatal period. Cervicovaginal mesenchyme induced p63 in Müllerian duct epithelium and subsequent squamous differentiation. In p63(-/-) mice, cervicovaginal epithelium differentiated into uterine epithelium. Thus, p63 is an identity switch for Müllerian duct epithelium to be cervicovaginal versus uterine. P63 was also essential for uterine squamous metaplasia induced by DES-exposure. DES-exposure from postnatal day 1 to 5 inhibited induction of p63 in cervicovaginal epithelium via epithelial ERalpha. The inhibitory effect of DES was transient, and most cervicovaginal epithelial cells recovered expression of p63 by 2 days after discontinuation of DES-treatment. However, some cervicovaginal epithelial cells failed to express p63, remained columnar and persisted into adulthood as adenosis.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Animals, Newborn
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Cell Differentiation / physiology*
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Cells, Cultured
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Cervix Uteri / cytology
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Cervix Uteri / drug effects
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Cervix Uteri / pathology*
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Cervix Uteri / physiology
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DNA-Binding Proteins
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Diethylstilbestrol / pharmacology*
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Embryo, Mammalian / anatomy & histology
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Embryo, Mammalian / physiology
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Epithelial Cells / cytology
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Epithelium / anatomy & histology
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Epithelium / drug effects*
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Epithelium / metabolism
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Epithelium / pathology
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Estrogen Receptor alpha
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Estrogens, Non-Steroidal / pharmacology*
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Female
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Genes, Tumor Suppressor
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Gestational Age
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Humans
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Mice
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Mice, Inbred Strains
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Mice, Knockout
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Mullerian Ducts / cytology
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Mullerian Ducts / physiology*
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Phenotype
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Phosphoproteins / metabolism*
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Pregnancy
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Receptors, Estrogen / metabolism
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Trans-Activators / metabolism*
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Transcription Factors
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Tumor Suppressor Proteins
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Uterine Cervical Neoplasms / pathology
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Uterine Neoplasms / pathology
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Uterus / cytology
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Uterus / drug effects
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Uterus / pathology
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Uterus / physiology
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Vagina / cytology
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Vagina / drug effects
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Vagina / pathology*
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Vagina / physiology
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Vaginal Neoplasms / pathology
Substances
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DNA-Binding Proteins
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Estrogen Receptor alpha
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Estrogens, Non-Steroidal
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Phosphoproteins
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Receptors, Estrogen
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TP63 protein, human
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Trans-Activators
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Transcription Factors
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Trp63 protein, mouse
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Tumor Suppressor Proteins
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Diethylstilbestrol