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, 97 (11), 5936-41

Estrogen Receptor (ER) Beta, a Modulator of ERalpha in the Uterus

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Estrogen Receptor (ER) Beta, a Modulator of ERalpha in the Uterus

Z Weihua et al. Proc Natl Acad Sci U S A.

Abstract

Many of the effects of estrogens on the uterus are mediated by ERalpha, the predominant ER in the mature organ. Because of the poor reproductive capacity of ERbeta knockout (BERKO) female mice (small litter size, multiple-resorbed fetuses), the role of uterine ERbeta was explored. In the immature uterus, ERalpha and ERbeta are expressed at comparable levels in the epithelium and stroma, and 17beta-estradiol (E(2)) treatment decreases ERbeta in the stroma. The immature uterus of untreated BERKO mice exhibits elevated levels of progesterone receptor (PR) and the proliferation-associated protein, Ki-67. It also exhibits exaggerated responsiveness to E(2), as indicated by enlargement of the lumen, increase in volume and protein content of uterine secretion, induction of the luminal epithelial secretory protein, complement C3, and its regulatory cytokine IL-1beta, and induction of vascular endothelial growth factor and insulin-like growth factor 1 but not its receptor. As expected, E(2) increased PR in the stroma and decreased it in the luminal epithelium of wild-type mice. In the BERKO uterus, E(2) induced PR in the stroma but did not down-regulate it in the epithelium. Increased cell proliferation and exaggerated response to E(2) in BERKO suggest that ERbeta plays a role in modulation of the effects of ERalpha and in addition (or as a consequence of this) has an antiproliferative function in the immature uterus.

Figures

Figure 1
Figure 1
Gross anatomic and histological comparison of uteri of immature BERKO (−/−) and wild-type (+/+) mice. (A) Gross anatomy of control (Con) and E2-treated (E2) uteri. Arrow indicates the transparent and fluid-filled E2-treated BERKO uterus compared with that of the wild type. (B) Histology of control and E2-treated uteri under the light microscope. Note the increased number of glands in the BERKO.
Figure 2
Figure 2
Protein and mRNA analysis of uterine secretion. (A) SDS/PAGE of secreted proteins from estradiol-treated BERKO (−/−) and wild-type (+/+) uteri. Lanes 1 and 3 contain the same amount of protein; lanes 2 and 4 contain the same volume of uterine fluid. (B) RT-PCR analyses of C3 and IL-1β in the uterus of immature BERKO and wild type. β-Actin was used as internal control (M, molecular size marker).
Figure 3
Figure 3
ERα and ERβ expression in response to E2 treatment in the wild-type uterus. (A) RT-PCR detection of ERα and ERβ mRNA. (B) Detection of ERβ by immunofluorescent labeling. (L, lumen; S, stroma; and LE, luminal epithelium). Total nuclei in the same section are indicated by fluorescence detection of 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI).
Figure 4
Figure 4
(A) Detection of Ki-67 by immunohistochemical staining in the immature BERKO and wild-type uterus. Positive nuclear staining is brown; slides were counterstained with hematoxylin. (B) Comparison of Ki-67 positive proportions; * and ** indicate significant differences between line-linked groups (n = 3; error bar, SD; *, P < 0.01; **, P < 0.05, t-test). (Con +/+, wild-type control; Con −/−, BERKO control; E2 +/+, wild-type E2 treated; E2 −/−, BERKO E2 treated).
Figure 5
Figure 5
Regulation of PR by E2 in the BERKO and wild-type immature uterus. Positive nuclear staining is brown; slides were counterstained with hematoxylin. Note the higher expression of PR in the BERKO uterus in both epithelium and stroma, and that E2 treatment down-regulates PR in the luminal epithelial cells of wild-type but not BERKO uteri. (Con +/+, wild-type control; Con −/−, BERKO control; E2 +/+, wild-type E2 treated; E2 −/−, BERKO E2 treated; arrow, luminal epithelium; arrowhead, glandular epithelium).
Figure 6
Figure 6
Detection of IGF-1, IGF-1Rβ, and VEGF in the BERKO and wild-type immature uterus. (A) RT-PCR analysis of IGF-1A (157 bp) and -1B (209 bp); β-actin was used as an internal control. (B) Immunohistochemical staining of IGF-1Rβ. (C) Immunohistochemical staining of VEGF. (Con +/+, wild-type control; Con −/−, BERKO control; E2 +/+, wild-type E2 treated; E2 −/−, BERKO E2 treated).

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