Abstract
Diethylstilbestrol (DES) is a synthetic estrogen and proven human teratogen and carcinogen reported to act via the estrogen receptor α (ERα). Since the endogenous ERα ligand 17β-estradiol (E2) does not show these adverse effects to a similar extent, we hypothesized that DES’ interaction with the ERα differs from that of E2. The current study aimed to investigate possible differences between DES and E2 using in vitro assays that detect ERα-mediated effects, including ERα-mediated reporter gene expression, ERα-mediated breast cancer cell (T47D) proliferation and ERα-coregulator interactions and gene expression in T47D cells. Results obtained indicate that DES and E2 activate ERα-mediated reporter gene transcription and T47D cell proliferation in a similar way. However, significant differences between DES- and E2-induced binding of the ERα to 15 coregulator motifs and in transcriptomic signatures obtained in the T47D cells were observed. It is concluded that differences observed in binding of the ERα with several co-repressor motifs, in downregulation of genes involved in histone deacetylation and DNA methylation and in upregulation of CYP26A1 and CYP26B1 contribute to the differential effects reported for DES and E2.
Highlights
Diethylstilbestrol (DES) is a synthetic estrogen that has been used from the 1940s to the 1970s to prevent premature delivery and fetal death by stimulating the synthesis of estrogen and progesterone in the placenta (IARC 2012)
The estrogen receptor α (ERα) agonist action has generally been associated with stimulation of cell proliferation, while estrogen receptor β (ERβ) activation has been linked with suppression of cell proliferation and stimulation of apoptosis (Sotoca et al 2008; Thomas and Gustafsson 2011)
Adverse effects of DES have been reported to be mediated via the ERα (Couse et al 2001; Couse and Korach 2004; Prins et al 2001)
Summary
Diethylstilbestrol (DES) is a synthetic estrogen that has been used from the 1940s to the 1970s to prevent premature delivery and fetal death by stimulating the synthesis of estrogen and progesterone in the placenta (IARC 2012). From 1971 onwards, the use of DES was prohibited since it was shown to induce rare reproductive tract cancers in women exposed in utero, while no protective effect against miscarriage and premature delivery was observed (Titus-Ernstoff et al 2001). Adverse effects included breast cancer, clear cell adenocarcinoma of the vagina and cervix, abnormalities in the female genital tract and abnormalities of the male reproductive tract (Colton and Greenberg 1982; Palmer et al 2006). DES is an analogue of the endogenous female sex hormone 17β-estradiol (E2) and binds to both the estrogen receptor α (ERα) and estrogen receptor β (ERβ) (Bolger et al 1998; Nikov et al 2001). The ERα agonist action has generally been associated with stimulation of cell proliferation, while ERβ activation has been linked with suppression of cell proliferation and stimulation of apoptosis (Sotoca et al 2008; Thomas and Gustafsson 2011)
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