Inhibitory Cross-Talk between Steroid Hormone Receptors: Differential Targeting of Estrogen Receptor in the Repression of Its Transcriptional Activity by Agonist- and Antagonist-Occupied Progestin Receptors

Kraus, W. Lee; Weis, Karen E.; Katzenellenbogen, Benita S.

doi:10.1128/mcb.15.4.1847

Cited by 183 publications

(99 citation statements)

References 41 publications

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“…This discrepancy results most likely from di erences in the cell type and the promoter context used for analysis and in the relative expression of transcriptional machinery (co-factors and co-repressors). Results obtained in MCF-7 and in BT-20 cells (in relation with in vivo data) are in agreement with the general opposing action of estrogens and progestins (Kraus et al, 1995), but this antagonism seems to be less clear in HBL-100 cells. In fact, Kraus et al (1995) and more recently Giangrande et al (1997) mentioned that the molecular mechanism(s) whereby progestins antagonize estrogen actions has not been clearly elucidated.…”

Section: Discussionsupporting

confidence: 78%

“…It is known that estrogens are required for converting the ERa to a transcriptionally active form able to stimulate many genes (Kraus et al, 1995). Furthermore, numerous data indicate that nuclear receptors, in particular the estrogen receptor, can be activated in the absence of their speci®c ligand (Weigel and Zhang, 1998;El Tanani and Green, 1997;Lee and Yee, 1995).…”

Section: Discussionmentioning

confidence: 99%

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Steroid hormones modulate H19 gene expression in both mammary gland and uterus

et al. 1999

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H19 is an imprinted and developmentally regulated gene whose product remains apparently untranslated. In a previous study on breast adenocarcinomas, we reported that overexpression of the H19 gene was signi®cantly correlated with the presence of steroid receptors, suggesting the putative role of hormones in H19 transcription. To determine the mode of steroid action, we have detected levels of H19 RNA synthesis during mammary gland development by in situ hybridization (ISH): two peaks of H19 transcription occur during puberty and pregnancy. Furthermore, we demonstrated by ISH that in the uterus H19 RNA synthesis is high during estrus and metestrus phases. To test steroid control of H19 transcription, ovariectomized and adrenalectomized mice were supplemented, 1 week after surgery, with 17-b-estradiol (E2, 20 mg/kg/day), progesterone (P, 1 mg/kg/day) or corticosterone (B, 0.3 mg/ kg/day) for 2 weeks. According to ISH data, E2 and to a lesser extent B stimulated H19 transcription in the uterus, whereas P inhibited it. To con®rm the in vivo results, in vitro experiments were performed using cultures of MCF-7 cells (a hormone-sensitive mammary cell line). E2 stimulated the endogenous H19 gene of this cell line and tamoxifen inhibited this e ect. Furthermore, we performed transient cotransfections in MCF-7, in HBL-100 (another hormone-sensitive mammary cell line) and in BT-20 (a hormone-insensitive mammary cell line) with various constructs of ERa (WT or mutated) and PR-A, in presence or absence of steroid hormones. We demonstrated that ERa up-regulated the H19 promoter in MCF-7 and in HBL-100, whereas PR-A did not have any e ect per se. Moreover, in MCF-7, PR-A antagonized clearly the ERa-mediated promoter enhancement, but in HBL-100 this counteracting e ect on the ERa up-regulation was not found. Interestingly, the same experiments performed in BT-20 cell line provided very similar results as those obtained in MCF-7 cells, with a clear down-regulation mediated by PR-A on the H19 promoter. All these in vitro data are in agreement with in vivo results. In addition, data obtained with ERa mutants indicate that H19 promoter activation is both ligand-dependent and ligand-independent. We have thus demonstrated that H19 gene expression is controlled by steroid hormones; furthermore, this gene is highly expressed in hormone-sensitive organs when the hormonal stimulation is accompanied with a morphological repair.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Steroid hormones modulate H19 gene expression in both mammary gland and uterus

et al. 1999

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“…This is di erent from other studies that demonstrated that the liganded PR could have potent inhibitory e ects on various transcriptional activators (Kraus et al, 1995). The vector used in the present experiment expresses PR-B, the dominant activator of progesterone-responsive target genes.…”

Section: Suppression Of Er Inhibits the Transforming Potentials Of Mucontrasting

confidence: 74%

Contribution of enhanced transcriptional activation by ER to [12Val] K-Ras mediated NIH3T3 cell transformation

et al. 1997

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We investigated the biological signi®cance of estrogen receptors (ER) in NIH3T3 cell transformation by the [ 12 Val] K-Ras mutant. This mutant enhanced the steady state level of ER. Cells expressing mutant K-Ras (K12V cell) were tumorigenic. To determine the role of ER accumulation in Ras-transformed cells, we developed cells (KwtER cells) that overexpressed both wild-type (wt) K-Ras and ER, and found these cells were also tumorigenic. E 2 stimulated the transcriptional activity by ER dominantly in K12V cells. However, only partial activation of ER by E 2 was seen in KwtER cells. In the presence of 10% serum in media, the activation of ER appeared only in transformed KtwER and K12V cells, suggesting that two independently transmitted signals, the E 2 -ER binding and the ER-AF1 activation, are necessary for ER activation and that the dominant activation of ER might be involved in Ras-mediated cell transformation. Co-expression of progesterone receptor (PR) with mutant K-Ras led to suppression of tumorigenicity and inhibition of the activation of ER. The antisense oligomers complementary to the ER suppressed proliferation and transformed phenotypes of K12V cells. These observations support the importance of ER in Ras-mediated cell transformation.

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“…Progesterone, in the presence of a functional PR, can inhibit transcription of the ER gene. 74 The higher progesterone levels in premenopausal women 54 could result in lower ER expression, but only in the presence of PR, which represents less than 50% of the breast carcinomas in premenopausal women. Some peptide hormones, cytokines and growth factors have been shown to alter ER expression 60 and may be present at different levels in pre-and postmenopausal women.…”

Section: Hormone Receptors and Breast Cancer Proliferationmentioning

confidence: 99%

Hormone receptors and proliferation in breast carcinomas of equivalent histologic grades in pre‐ and postmenopausal women

Talley

Grizzle

Waterbor

et al. 2001

Intl Journal of Cancer

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Breast cancers in younger, premenopausal women are more likely to exhibit an adverse prognostic profile (including negative steroid hormone receptors and a high rate of cellular proliferation) and poor outcome than breast cancers in postmenopausal women. It has been hypothesized that this adverse prognostic profile is a result of the higher histologic grade of breast cancers in pre-compared with post-menopausal women. To assess the association of expression of steroid hormone receptors and indicators of proliferation while controlling for histologic grade, we identified 100 infiltrating ductal carcinomas from premenopausal women 45 years of age or younger and 100 from postmenopausal women 65 years of age or older. The carcinomas were selected so that the histologic grades (low versus high) were distributed equally between the 2 groups. Estrogen receptors (ER), progesterone receptors (PR), p27 Kip1 and Ki-67 (to measure rate of proliferation) were assessed by immunohistochemistry and compared between groups. Clinical information and survival data were also analyzed. ER content was lower and proliferation was higher in carcinomas in premenopausal women (p ‫؍‬ 0.048 and p ‫؍‬ 0.005, respectively). By univariate analysis, p27 Kip1 and PR were not different between the groups; however, in multivariate analysis, p27 Kip1 was higher in postmenopausal women, but only in a subgroup with highly proliferative carcinomas. Overall survival was similar in the pre-and postmenopausal women. Furthermore, low p27 Kip1 and African-American ethnicity predicted a poorer overall survival in the premenopausal, but not in the postmenopausal, women in our study. After controlling for histologic grade, a lower expression of ER and a higher proliferative index were detected in breast carcinomas in premenopausal women. Therefore, some prognostic indicators, such as ER and proliferative rate, may be more closely associated with menopausal status than histologic grade. Our data also suggest that some prognostic factors are not equally effective as predictors of survival in pre-and postmenopausal women. Prognosis in women with breast cancer has been reported to differ according to age and menopausal status. Studies examining this issue have varied in design, age categorization and outcome measures. A few large population-based studies and more limited analyses 1-5 have indicated that women under the ages of 30 -40 years have a worse prognosis. Some retrospective studies have attempted to explain the less favorable outcome in younger women and have reported that breast cancers in younger women exhibit more adverse characteristics, including a high clinical stage at diagnosis, high histologic grade, lack of steroid hormone receptors and increased proliferation. 6 -9 Multivariate analyses to assess associations of age and menopausal status with other clinical and pathologic characteristics have not consistently retained either variable as an independent adverse prognosticator, 8 although several multivariate analyses have indicated that young ag...

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Inhibitory Cross-Talk between Steroid Hormone Receptors: Differential Targeting of Estrogen Receptor in the Repression of Its Transcriptional Activity by Agonist- and Antagonist-Occupied Progestin Receptors

Cited by 183 publications

References 41 publications

Steroid hormones modulate H19 gene expression in both mammary gland and uterus

Steroid hormones modulate H19 gene expression in both mammary gland and uterus

Contribution of enhanced transcriptional activation by ER to [12Val] K-Ras mediated NIH3T3 cell transformation

Hormone receptors and proliferation in breast carcinomas of equivalent histologic grades in pre‐ and postmenopausal women

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