Canonical Wnt Signaling Is Critical to Estrogen-Mediated Uterine Growth

Abstract

Major biological effects of estrogen in the uterus are thought to be primarily mediated by nuclear estrogen receptors, ERalpha and ERbeta. We show here that estrogen in an ER-independent manner rapidly up-regulates the expression of Wnt4 and Wnt5a of the Wnt family and frizzled-2 of the Wnt receptor family in the mouse uterus. One of the mechanisms by which Wnts mediate canonical signaling involves stabilization of intracellular beta-catenin. We observed that estrogen treatment prompts nuclear localization of active beta-catenin in the uterine epithelium. We also found that adenovirus mediated in vivo delivery of SFRP-2, a Wnt antagonist, down-regulates estrogen-dependent beta-catenin activity without affecting some of the early effects (water imbibition and angiogenic markers) and inhibits uterine epithelial cell growth, suggesting that canonical Wnt signaling is critical to estrogen-induced uterine growth. Our present results provide evidence for a novel role of estrogen that targets early Wnt/beta-catenin signaling in an ER-independent manner to regulate the late uterine growth response that is ER dependent.

Puerarin, a selective oestrogen receptor modulator, disrupts pregnancy in rats at pre-implantation stage

“…Post-coital contraceptive potential of puerarin evidence suggests that oestrogen-mediated uterine events for implantation are primarily mediated via nuclear receptors. Oestrogen mediates its effects by two ER subtypes, ERa and ERb (Hou et al 2004). The mRNA of the two ER subtypes coexists in the rat uterus during pregnancy (Minorics et al 2004), but the process of embryo implantation possibly involves ERa-mediated endometrial effects (Ma et al 2003).…”

“…Implantation is a crucial step in the process of establishment of pregnancy, and in rats and mice, it involves participation of oestrogens to a significant extent (Psychoyos 1973). The effects of oestrogens appear to be mediated by two oestrogen receptor subtypes, ERa and ERb (Hou et al 2004). The intriguing biology of oestrogens on different target cells is determined by the structure of the ligand and the ER subtype involved.…”

Involvement of β-catenin and unusual behavior of CBP and p300 in glucocorticosteroid signaling in Schwann cells

“…The role of ␤-catenin as a coactivator of androgen receptor has been well established in prostate cancer cells. Through their interaction, ␤-catenin augments androgen receptor (AR)-mediated transcription (29)(30)(31)(32)(33), and a functional interaction between ER ␣-and ␤-catenin has also been recently described in human colon and breast cancer cells (13) and uterus (34).…”

Uterine sensing of the embryo

“…Thus, the notion that Wnt7a is derived from the embryo is consistent with previous studies. Nonetheless, canonical Wnt signaling is needed for embryoindependent, estrogen-stimulated uterine growth in the mouse (5). As is the case for implantation-associated events, these studies demonstrated that sFRP-2 blocks these responses.…”