Expression of a dominant negative estrogen receptor alpha variant in transgenic mice accelerates uterine cancer induced by the potent estrogen diethylstilbestrol

DOI

10.1016/j.reprotox.2012.08.005

Document Type

Journal Article

Publication Date

12-1-2012

Publication Title

Reproductive Toxicology

Volume

34

Issue

4

First Page

512

Last Page

521

ISSN

8906238

Keywords

Diethylstilbestrol, Dominant negative receptor, ERΔ3, ERα variants, Lactoferrin, Non-classical ER signaling, Progesterone receptor, Uterine cancer

Abstract

ERΔ3 transgenic mice expressing a dominant negative estrogen receptor α (ERα) variant lacking the second zinc finger in the DNA binding domain were developed to examine its potential to inhibit estrogen action in vivo. To investigate if ERΔ3 expression influences uterine carcinogenesis, ERΔ3 transgenic mice were exposed to diethylstilbestrol (DES) on post-natal days 1-5. Neonatal DES treatment induced uterine adenocarcinomas in 81% of 8-month-old ERΔ3 mice compared to 49% of wild-type females (p< 0.016). ERΔ3 did not inhibit the expression of the estrogen-responsive progesterone receptor and lactoferrin genes in the presence of ERα or modify their expression in ERα knockout (αERKO) mice. Higher circulating 17β-estradiol levels and non-classical signaling by ERΔ3 may be related to the earlier incidence of uterine cancer. These findings indicate that expression of this ERα variant can influence determining events in uterine cancer development and its natural occurrence in the human uterus would unlikely be protective. © 2012.

Open Access

Green Accepted

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