Roles of p63 in the DES-induced cervicovaginal adenosis

The p63 gene expression is permanently changed by DES

2004 Study 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.

Wnt7a has been suggested as an immediate target of DES in development of vaginal adenosis because Wnt7a was downregulated by DES in the Müllerian duct, and the Wnt7a–/– mouse developed  vaginal adenosis.

In DES-daughters, cervical/vaginal clear cell adenocarcinoma is rare, even though cervical/vaginal adenosis is commonly found. Although adenosis is thought to be the substrate from which clear cell adenocarcinoma develops, the mechanism by which adenosis develops into adenocarcinoma is unclear. We have shown that DES actions on the p63–/– cervicovaginal mesenchyme (CVM) do not play a role in formation of adenosis. However, growth, cell death and differentiation of epithelial tissue in the female reproductive tract are regulated by stromal cells during embryogenesis as well as adult period. Thus, it is likely that the DES-caused changes in the stromal cells also play important roles in the subsequent development of cervicovaginal adenocarcinoma.

Sources and more information
  • Roles of p63 in the diethylstilbestrol-induced cervicovaginal adenosis, Development (Cambridge, England), NCBI PubMed PMID: 14998922, 2004 Apr.
    Full study via The Company of Biologists Ltd, doi:10.1242/dev.01038, 2004.
  • Models for Müllerian duct epithelial differentiation featured image credit The Company of Biologists Ltd .

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