Regulation of Estrogen Target Genes and Growth by Selective Estrogen-Receptor Modulators in Endometrial Cancer Cells

Dardes, Rita C.; Schafer, Jennifer Mac Gregor; Pearce, Sandra Timm; Osipo, Clodia; Chen, B.; Jordan, V. Craig

doi:10.1006/gyno.2002.6659

Cited by 45 publications

(29 citation statements)

References 33 publications

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“…By contrast, estrogens in the culture medium proved to be strong repressors of ER-alpha production by hTERT-EECs. Down-regulation of ER-alpha following estrogen treatment has recently been shown in endometrial glands of ovariectomized macaques (Wang et al 2002), in endometrial epithelial and stromal cells of immature ewes (Meikle et al 2000) and in the human endometrial carcinoma cell line ECC-1 (Dardes et al 2002). hTERT-EECs produced a functional ER-alpha that was clearly responsive to estrogen or the synthetic estrogenic compound DES, as demonstrated by a strong induction of luciferase using a ERE-luciferase reporter plasmid.…”

Section: Steroid Hormone-responsive Htert-eecs · S Hombach-klonisch Amentioning

confidence: 93%

“…There are conflicting results on the expression of ER-alpha within human EECs (Marshburn et al 1992, Zhang et al 1995, Dardes et al 2002. The hTERTEECs showed a down-regulation at the gene and protein level of ER-alpha by its ligand E2.…”

Section: Steroid Hormone-responsive Htert-eecs · S Hombach-klonisch Amentioning

confidence: 99%

“…The human endometrial carcinoma cell lines Ishikawa, RL-95, ECC-1, KLE, HEC-1A and EN revealed altered or impaired hormonal responsiveness (Thie et al 1995, Jazaeri et al 2001, Dardes et al 2002, Di Nezza et al 2003, Farnell & Ing 2003, Isaka et al 2003. In hTERT-EECs, the level of expression of ER-alpha, but not ER-beta, was regulated by estrogen, demonstrating different regulatory processes to affect the transcriptional activation of the two human ER isoforms in hTERT-EECs.…”

Section: Steroid Hormone-responsive Htert-eecs · S Hombach-klonisch Amentioning

confidence: 99%

“…In addition, the process of dedifferentiation includes down-regulation of steroid hormone receptors (Schatz et al 1990, White et al 1990). However, due to the lack of experimental models retaining steroid hormone responsiveness there is conflicting evidence on the effects of 17 beta-estradiol (E2) on EECs (Marshburn et al 1992, Zhang et al 1995, Dardes et al 2002.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of functional steroid receptors and ligand-induced responses in telomerase-immortalized human endometrial epithelial cells

Hombach‐Klonisch¹,

Kehlen²,

Fowler³

et al. 2005

Journal of Molecular Endocrinology

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Information on the regulation of steroid hormone receptors and their distinct functions within the human endometrial epithelium is largely unavailable. We have immortalized human primary endometrial epithelial cells (EECs) isolated from a normal proliferative phase endometrium by stably transfecting the catalytic subunit (hTERT) of the human telomerase complex and cultured these hTERT-EECs now for over 350 population doublings. Active hTERT was detected in hTERT-EECs employing the telomerase repeat amplification assay protocol. hTERT-EECs revealed a polarized, non-invasive epithelial phenotype with apical microvilli and production of a basal lamina when grown on a three-dimensional collagen-fibroblast lattice. Employing atomic force microscopy, living hTERT-EECs were shown to produce extracellular matrix (ECM) components and ECM secretion was modified by estrogen and progesterone (P4). hTERT-EECs expressed inducible and functional endogenous estrogen receptor-alpha (ER-alpha) as demonstrated by estrogen response element reporter assays and induction of P4 receptor (PR). P4 treatment down-regulated PR expression, induced MUC-1 gene activity and resulted in increased ER-beta transcriptional activity. Gene activities of cytokines and their receptors interleukin (IL)-6, leukemia inhibitory factor (LIF), IL-11 and IL-6 receptor (IL6-R), LIF receptor and gp130 relevant to implantation revealed a 17 beta-estradiol (E2)-mediated up-regulation of IL-6 and an E2-and P4-mediated up-regulation of IL6-R in hTERT-EECs. Thus, hTERT-EECs may be regarded as a novel in vitro model to investigate the role of human EECs in steroid hormone-dependent normal physiology and pathologies, including implantation failure, endometriosis and endometrial cancer.

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Section: Steroid Hormone-responsive Htert-eecs · S Hombach-klonisch Amentioning

confidence: 93%

Section: Steroid Hormone-responsive Htert-eecs · S Hombach-klonisch Amentioning

confidence: 99%

Section: Steroid Hormone-responsive Htert-eecs · S Hombach-klonisch Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Regulation of functional steroid receptors and ligand-induced responses in telomerase-immortalized human endometrial epithelial cells

Hombach‐Klonisch¹,

Kehlen²,

Fowler³

et al. 2005

Journal of Molecular Endocrinology

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“…Estudos mostraram que o raloxifeno bloqueia a concentração das proteínas PS2 e C3, parâme-tros da expressão gênica induzida pelo estrogênio, em cultura de células ECC1 (linhagem de adenocarcinoma endometrial humano bem diferenciado) 13 . Dardes et al 14 relataram que o raloxifeno diminui a expressão de proteínas do receptor alfa de estrogênio, o que pode justificar a ação antagonista deste SERM; além disso, mostraram também que o raloxifeno bloqueia parcialmente o efeito proliferativo dos estrogênios nas células ECC1 in vitro.…”

Section: Introductionunclassified

Efeitos da terapia estro-raloxifeno sobre o endométrio de ratas

Moraes

Simões

Fonzar

et al. 2006

Rev. Bras. Ginecol. Obstet.

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RESUMOObjetivo: avaliar os efeitos dos estrogênios conjugados eqüinos (Ece) e do raloxifeno (Ral), isoladamente ou associados, sobre o endométrio de ratas adultas. Métodos: foram utilizadas 56 ratas adultas, ooforectomizadas, divididas aleatoriamente em sete grupos: GCont (controle); GEce (Ece 50 μg/kg); GEce/25 (Ece 25 μg/kg); GRal/0,75 (Ral 0,75 mg/kg); GRal/0,4 (Ral 0,4 mg/kg); GEce-Ral (50/0,75) -(Ece 50 μg/kg + Ral 0,75 mg/kg) e GEce-Ral (25/0,4) -(Ece 25 μg/kg + Ral 0,4 mg/kg). As drogas foram administradas por gavagem durante 21 dias consecutivos. Ao final da administração todos os animais foram anestesiados e fragmentos dos úteros removidos, fixados em formol a 10% e processados para inclusão em parafina. Os cortes obtidos foram corados por HE e submetidos à avaliação histomorfométrica. Foram avaliados os seguintes parâmetros: espessura do epitélio superficial, número de glândulas endometriais/mm 2 e número de vasos sangüíneos presentes no miométrio/mm 2 . Os dados obtidos foram submetidos a análise estatística de ANOVA seguida pelo teste de Tukey-Kramer. Resultados: nos grupos controle (Gcont) e tratados isoladamente com raloxifeno (GRal/0,75 e GRal/0,4) o endométrio mostrou-se atrófico. Já nos grupos tratados com Ece isoladamente foi observado endométrio muito desenvolvido, sendo este efeito mais acentuado no grupo que recebeu 50 μg/kg, no qual encontramos aumento da espessura do epitélio superficial e da lâmina própria e no número de glândulas endometriais e de vasos sanguíneos. Notamos também proliferação endometrial nos grupos que receberam a associação de Ece e Ral (GEce-Ral -50/0,75) e (GEce-Ral -25/0,4). Conclusão: o raloxifeno parece bloquear parcialmente a ação do estrogênio no endométrio de ratas adultas castradas. PALAVRAS-CHAVE:Raloxifeno; Estrogênios; Terapia de reposição hormonal; Endométrio ABSTRACT Purpose: to evaluate the effects of conjugated equine estrogens (CEE) and raloxifene (Ral), alone or combined, on the rat endometrium. Methods: fifty-six adult rats were ovariectomized and randomly divided into seven groups: GCont (control); GCEE (CEE 50 μg/kg); GCEE/25 (CEE 25 μg/kg); GRal/0.75 (Ral 0.75 mg/kg); GRal/0.4 (Ral 0.4 mg/kg); GCEE-Ral (50/0.75) -(CEE 50 μg/kg + Ral 0.75 mg/kg), and GCEE-Ral (25/0.4) -(CEE 25 μg/kg + Ral 0.4 mg/kg). The drugs were orally administered (gavage) for 21 consecutive days. At the end of the experiment, all animals were anesthetized and sacrificed. Fragments of uterus were removed, fixed in 10% formaldehyde and processed for paraffin inclusion. The histological sections were stained by HE and submitted to histomorphometric evaluation. The following parameters were analyzed: thickness of superficial epithelium and number of endometrial glands/mm 2 and of blood vessels/mm 2 . The data were evaluated using ANOVA followed by the Turkey-Kramer test. Results: in the GCont and only Ral treatment (GRal/0.75 and GRal/0.4) the endometrium showed signals of atrophy. In the groups treated with only CEE signs of endometrial proliferation were observed, mainly in group...

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The effects of the selective estrogen receptor modulators, methyl‐piperidino‐pyrazole (MPP), and raloxifene in normal and cancerous endometrial cell lines and in the murine uterus

Davis

Ellersieck

Grimm

et al. 2006

Molecular Reproduction Devel

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Since estrogens have vital functions in the uterus but might also contribute to endometrial cancer, we sought to determine the in vitro effects of methyl-piperidino-pyrazole (MPP), raloxifene, and beta-estradiol on Ishikawa and RL-95 endometrial cancer, and ovine luminal endometrial (oLE) cell lines and the in vivo effects of these compounds in the rodent uterus. MPP and raloxifene (1 nM) induced significant apoptosis in the endometrial cancer and oLE cell lines compared to beta-estradiol treated and control cells (P

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Regulation of Estrogen Target Genes and Growth by Selective Estrogen-Receptor Modulators in Endometrial Cancer Cells

Cited by 45 publications

References 33 publications

Regulation of functional steroid receptors and ligand-induced responses in telomerase-immortalized human endometrial epithelial cells

Regulation of functional steroid receptors and ligand-induced responses in telomerase-immortalized human endometrial epithelial cells

Efeitos da terapia estro-raloxifeno sobre o endométrio de ratas

The effects of the selective estrogen receptor modulators, methyl‐piperidino‐pyrazole (MPP), and raloxifene in normal and cancerous endometrial cell lines and in the murine uterus

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