2003
DOI: 10.1073/pnas.0731830100
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Disruption of the estrogen receptor β gene in mice causes myeloproliferative disease resembling chronic myeloid leukemia with lymphoid blast crisis

Abstract: Proliferation of pluripotent, bone marrow stem cells, which develop to lymphoid and myeloid progenitors, is negatively regulated by estrogen. Although in estrogen deficiency and in estrogen receptor knockout mice there is significant alteration in bone marrow hematopoiesis, the effects of aging on estrogen receptor deficiencies in mice have not been investigated yet. In this study we show that by 1.5 years of age, estrogen receptor ␤ knockout (ER␤ ؊/؊ ) mice develop pronounced splenomegaly that is much more se… Show more

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Cited by 156 publications
(115 citation statements)
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“…For example, five of the compounds identified in this screen (dimaprit dihydrochloride, pergolide methanesulfonate, (R)-(-)-apomorphine HCl, erythro-9-(2-hydroxy-3-nonyl) adenine HCl and the β-estradiol-related compound 16-ketoestradiol) increase intracellular cyclic AMP, which in turn potentiates myeloid differentiation [13][14][15][16][17][18] . The fact that the estrogen derivative 16-ketoestradiol had differentiation-promoting activity prompted us to examine structurally related compounds, including β-estradiol, 17-α-ethynylestradiol and 17-α-estradiol, all of which induced neutrophilic morphology and NBT reduction (P < 0.02; Supplementary Table 1o and Supplementary Note online), suggesting that it is the estrogenic component of these molecules that promotes differentiation, as previously suggested 19,20 . Two of the other compounds identified in this screen block pyrimidine synthesis through inhibition of either dihydrofolate reductase (aminopterin) or thymidylate synthetase (5-fluorouridine) 21,22 .…”
mentioning
confidence: 75%
“…For example, five of the compounds identified in this screen (dimaprit dihydrochloride, pergolide methanesulfonate, (R)-(-)-apomorphine HCl, erythro-9-(2-hydroxy-3-nonyl) adenine HCl and the β-estradiol-related compound 16-ketoestradiol) increase intracellular cyclic AMP, which in turn potentiates myeloid differentiation [13][14][15][16][17][18] . The fact that the estrogen derivative 16-ketoestradiol had differentiation-promoting activity prompted us to examine structurally related compounds, including β-estradiol, 17-α-ethynylestradiol and 17-α-estradiol, all of which induced neutrophilic morphology and NBT reduction (P < 0.02; Supplementary Table 1o and Supplementary Note online), suggesting that it is the estrogenic component of these molecules that promotes differentiation, as previously suggested 19,20 . Two of the other compounds identified in this screen block pyrimidine synthesis through inhibition of either dihydrofolate reductase (aminopterin) or thymidylate synthetase (5-fluorouridine) 21,22 .…”
mentioning
confidence: 75%
“…The function of ER-b is not completely understood and it has been suggested that the receptor, acting through estrogens, may protect normal prostate epithelial from undergoing unscheduled cell proliferation, neoplastic transformation and from oxidative injuries. 8,13,22,[28][29][30] Even though the expression of ER-b in early prostate carcinoma and also in high grade prostatic intraepithelial neoplasia is decreased compared to normal prostatic epithelium, and some authors have found in cell line studies that its forced expression inhibits invasion and proliferation and triggers apoptosis, 31 its expression in PCa cells seems to be associated with cell survival, is highly expressed in metastatic prostate carcinoma and in our previous study was also associated with higher Gleason grades. 8,15,[32][33][34] Of note, ER-b, via an AP1-like antioxidant response element, may regulate expression of quinone reductase, an enzyme implied in control of ROS and free radicals.…”
Section: Discussionmentioning
confidence: 53%
“…Although estrogens via ERa stimulates proliferation in the breast, uterus and developing prostate, [6][7][8] thereby increasing the risk of tumor development and progression, estrogens via ERb inhibit proliferation and promotes differentiation of the prostate, mammary gland, colon, lung and stem cells of the bone marrow. [9][10][11][12][13] An antiproliferative effect of ERb is also suggested from experiments in ERb knockout mice, which display a myeloproliferative disease resembling human chronic myeloid leukemia with lymphoid blast crisis and prostate hyperplasia, suggesting that ERb may act as a tumor suppressor. 9,13 Furthermore, transfection of ER-negative cancer cell lines with ERb also results in reduced proliferation.…”
Section: Introductionmentioning
confidence: 96%
“…[9][10][11][12][13] An antiproliferative effect of ERb is also suggested from experiments in ERb knockout mice, which display a myeloproliferative disease resembling human chronic myeloid leukemia with lymphoid blast crisis and prostate hyperplasia, suggesting that ERb may act as a tumor suppressor. 9,13 Furthermore, transfection of ER-negative cancer cell lines with ERb also results in reduced proliferation. 14,15 Cancers of the reproductive tissues, prostate and colon are well-known cancers to involve estrogen signaling.…”
Section: Introductionmentioning
confidence: 96%