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PubMed2004

Nutritional flavonoids modulate estrogen receptor alpha signaling.

Estrogen receptor alpha (ERalpha) mediates 17beta-estradiol (E2) actions through the transcription of E2-sensitive target genes. In addition, rapid non-genomic signaling (e.g., MAPK/ERK) occurs. It is now well accepted that these rapid membrane-initiated responses account for E2-related cancer. Beside many beneficial effects on human health, nutritional flavonoids exert protective and anticarcinogenic effects on E2-related cancer. The mechanism underlying these effects seems to be related to flavonoids antioxidant properties and/or to their ability to alter signal transduction protein kinases. In addition, an antiestrogenic activity has been proposed but not yet defined. However, the identification and characterization of the responsible mechanisms for flavonoid antitumoral effects is poorly understood. Here, we investigated the possibility that the antimitogenic effects of flavonoids are transduced by modulating ERalpha-mediated rapid signaling. The ability of two flavonoids, the flavanone naringenin and the flavanol quercetin, with respect of E2, to induce ERalpha activities has been studied in the human cervix epitheloid carcinoma cell line (HeLa) devoid of any estrogen receptors and rendered E2-sensitive by transient transfection with a human ERalpha expression vector. Our results indicate that flavonoids act as E2 mimetic on ERalpha transcriptional activity, whereas they impair the activation of rapid signaling pathways committed to E2-induced proliferation. The resulting decoupling of ERalpha signal transduction could be proposed as a new mechanism in the protective effects of flavonoids against E2-related cancer.

Cyclin D1↗
PubMed1998

Reproductive endocrine and endometrial effects of raloxifene hydrochloride, a selective estrogen receptor modulator, in women with regular menstrual cycles.

Previous studies of raloxifene conducted in animal models and postmenopausal women have demonstrated antiestrogenic action on the endometrium. The purpose of this first study of raloxifene in women with normal menstrual cycles was to determine its reproductive endocrine and endometrial effects. In part I, raloxifene (400 mg) was administered for 5 days in the follicular, periovulatory, or luteal phase of the menstrual cycle (n = 12). In part II, women were randomized to receive raloxifene (100 or 200 mg) for 28 days beginning on day 3 of the cycle (n = 19). All women ovulated in both parts of the study. Raloxifene did not alter the length of the menstrual cycle or the day of the LH surge. A 5-day course of raloxifene administered in any phase of the cycle elevated FSH area under the curve (AUC) for the entire cycle and estradiol AUC for the second half of the cycle compared with those in control cycles. In part II, raloxifene also appeared to increase the FSH AUC and estradiol AUC. Raloxifene decreased the number of gland mitoses in follicular phase endometrial biopsies. Subtle effects suggestive of gland-stromal dysynchrony were noted in a limited number of the secretory phase endometrial biopsies. This study has demonstrated that 1) raloxifene does not prevent ovulation in women with normal menstrual cycles; 2) ovarian estrogen production will continue, and in some cases increase, in response to raloxifene; and 3) antiestrogenic effects of raloxifene on the endometrium are subtle in the endocrine milieu of normal to high circulating estradiol concentrations.

Adult↗
PubMed2001

Centchroman, a selective estrogen receptor modulator, as a contraceptive and for the management of hormone-related clinical disorders.

DL-Centchroman (67/20; INN: Ormeloxifene) synthesized at the Central Drug Research Institute, Lucknow, is a nonsteroidal once-a-week oral contraceptive. It was introduced in Delhi in July, 1991, marketed in India in 1992 as Saheli and Choice-7 (Hindustan Latex Ltd., Thiruvananthapuram) and Centron (Torrent Pharmaceuticals India Ltd., Ahmedabad), and included in the National Family Welfare Programme in 1995.5 According to post-marketing surveillance, approximately 100,000 women were using this pill and approximately 1100,000 menstrual cycles were covered until 1996. It is a unique need-oriented contraceptive being effective when taken immediately after coitus or routinely as a weekly pill and has the advantage of less frequent administration. Its contraceptive action is quickly reversible. It has long terminal serum halflife of 168 hr in women and exhibits duration of anti-implantation/estrogen antagonistic action of 120 hr, despite a short (24.1 hr) serum halflife, in the rat. In lactating women, it is excreted in milk in quantities considered unlikely to cause any deleterious effect on suckling babies. In phase II and III multicentric trials as a contraceptive, children born of method-and-user failure pregnancies showed normal milestones, without any congenital anomaly. Reports of its promising action in the management of certain hormone-related clinical disorders are available. It has an excellent therapeutic index and is considered safe for chronic administration.

Animals↗
PubMed2001

Estrogen modulates estrogen receptor alpha and beta expression, osteogenic activity, and apoptosis in mesenchymal stem cells (MSCs) of osteoporotic mice.

In the mouse, ovariectomy (OVX) leads to significant reductions in cancellous bone volume while estrogen (17beta-estradiol, E2) replacement not only prevents bone loss but can increase bone formation. As the E2-dependent increase in bone formation would require the proliferation and differentiation of osteoblast precursors, we hypothesized that E2 regulates mesenchymal stem cells (MSCs) activity in mouse bone marrow. We therefore investigated proliferation, differentiation, apoptosis, and estrogen receptor (ER) alpha and beta expression of primary culture MSCs isolated from OVX and sham-operated mice. MSCs, treated in vitro with 10(-7) M E2, displayed a significant increase in ERalpha mRNA and protein expression as well as alkaline phosphatase (ALP) activity and proliferation rate. In contrast, E2 treatment resulted in a decrease in ERbeta mRNA and protein expression as well as apoptosis in both OVX and sham mice. E2 up-regulated the mRNA expression of osteogenic genes for ALP, collagen I, TGF-beta1, BMP-2, and cbfa1 in MSCs. In a comparison of the relative mRNA expression and protein levels for two ER isoforms, ERalpha was the predominant form expressed in MSCs obtained from both OVX and sham-operated mice. Cumulatively, these results indicate that estrogen in vitro directly augments the proliferation and differentiation, ERalpha expression, osteogenic gene expression and, inhibits apoptosis and ERbeta expression in MSCs obtained from OVX and sham-operated mice. Co-expression of ERalpha, but not ERbeta, and osteogenic differentiation markers might indicate that ERalpha function as an activator and ERbeta function as a repressor in the osteogenic differentiation in MSCs. These results suggest that mouse MSCs are anabolic targets of estrogen action, via ERalpha activation. J. Cell. Biochem. Suppl. 36: 144-155, 2001.

Alkaline Phosphatase↗
PubMed2001

Antidepressants do not modulate estrogen receptor alpha-mediated gene expression.

The estrogen receptor alpha has been shown to be activated both in a ligand-dependent and in a ligand independent fashion. We investigated whether antidepressants may directly activate the estrogen receptor alpha or enhance ligand-dependent or ligand-independent activation of the estrogen receptor alpha. Whereas both ligand-dependent and ligand-independent activation of the estrogen receptor alpha could be demonstrated in transient transfection studies, antidepressants neither directly activated the estrogen receptor alpha nor did they enhance ligand-dependent or ligand-independent activation. Thus, there are differences between the glucocorticoid receptor and the estrogen receptor alpha with regard to ligand-independent activation and action of antidepressants.

Animals↗
PubMed1985

Dexamethasone suppresses estrogen action at the pituitary level without modulating estrogen receptor dynamics.

The administration of glucocorticoid combined with antiestrogen such as clomiphene has been shown to be effective for the induction of ovulation in patients with anovulation. The present study was undertaken to examine the effects of glucocorticoid on estrogen-induced changes in the pituitary gland. A single intraperitoneal (i.p.) administration of 10 micrograms estradiol-17 beta (E2) in ovariectomized and adrenalectomized rats resulted in a significant stimulation of pituitaries with regard to wet tissue weight and progesterone receptor content. An i.p. administration of 1 mg dexamethasone in these animals had no effects on both the values. However, the E2-induced increases in pituitary weight and progesterone receptor content were significantly inhibited by pretreatment with 1 mg of dexamethasone. The pretreatment with dexamethasone, on the other hand, had no significant effect on the dynamics of pituitary estrogen receptor induced by the injection of E2, i.e. the degree of nuclear translocation, occupancy and cytoplasmic receptor replenishment. The inhibitory effect of dexamethasone, therefore, does not seem to be mediated through estrogen receptor system in the pituitary. These results suggest that dexamethasone acts directly on the pituitary gland to suppress the action of E2, and which may be involved in the process of induction of ovulation by glucocorticoid-clomiphene treatment.

Adrenalectomy↗
PubMed2003

Efficacy of Vitamin D compounds to modulate estrogen receptor negative breast cancer growth and invasion.

In estrogen receptor (ER) positive breast cancer cells such as MCF-7 cells, the anti-tumor effects of 1,25(OH)(2)D(3) (1,25D(3)) may be secondary to disruption of estrogen mediated survival signals. If so, then sensitivity to 1,25D(3) mediated growth arrest could be reduced in estrogen independent breast cancer cells. The aim of these studies was to determine the effects of 1,25D(3) and EB1089 on the ER negative, invasive human breast cancer cell line SUM-159PT. 1,25D(3) and EB1089 reduced SUM-159PT cell growth subsequent to elevation of p27 and p21 levels. 1,25D(3) mediated apoptosis of SUM-159PT cells was associated with an enrichment of membrane bound bax, a redistribution of cytochome c from the mitochondria to the cytosol and PARP cleavage. 1,25D(3) and EB1089 also inhibited SUM-159PT cell invasion through an 8 microM Matrigel membrane. In pre-clinical studies, EB1089 dramatically reduced the growth of SUM-159PT xenografts in nude mice. The decreased size of tumors from EB1089 treated mice was associated with decreased proliferation and increased DNA fragmentation. Our data support the concept that Vitamin D(3) compounds trigger apoptosis by mechanisms independent of estrogen signaling. These studies indicate that Vitamin D(3) based therapeutics may be beneficial, alone or in conjunction with other agents, for the treatment of estrogen independent breast cancer.

Animals↗
PubMed1998

Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action.

Regulation of gene activation by the estrogen receptor (ER) is complex and involves co-regulatory proteins, oncoproteins (such as Fos and Jun), and phosphorylation signaling pathways. Here we report the cloning and initial characterization of a novel protein, Brx, that contains a region of identity to the oncogenic Rho-guanine nucleotide exchange (Rho-GEF) protein Lbc, and a unique region capable of binding to nuclear hormone receptors, including the ER. Western and immunohistochemistry studies showed Brx to be expressed in estrogen-responsive reproductive tissues, including breast ductal epithelium. Brx bound specifically to the ER via an interaction that required distinct regions of ER and Brx. Furthermore, overexpression of Brx in transfection experiments using an estrogen-responsive reporter revealed that Brx augmented gene activation by the ER in an element-specific and ligand-dependent manner. Moreover, activation of ER by Brx could be specifically inhibited by a dominant-negative mutant of Cdc42Hs, but not by dominant negative mutants of RhoA or Rac1. Taken together, these data suggest that Brx represents a novel modular protein that may integrate cytoplasmic signaling pathways involving Rho family GTPases and nuclear hormone receptors.

A Kinase Anchor Proteins↗
PubMed2000

Estrogen-modulated estrogen receptor x Pit-1 protein complex formation and prolactin gene activation require novel protein synthesis.

Both estrogen receptor (ER) and Pit-1 proteins are essential for the estrogen-activated expression of the rat prolactin gene. Our results show that ER.Pit-1 protein complex formation is reduced by estrogen in GH3 and PR1 rat pituitary tumor cells. In the latter, this decrease was blocked by cycloheximide, a protein synthesis inhibitor. On the other hand, the direct addition of estrogen to PR1 cell lysates had no effect on the formation of ER.Pit-1 complexes. Estrogen-activated prolactin gene expression was also inhibited by cycloheximide, suggesting that some form of protein synthesis is involved in ER.Pit-1 complex formation and subsequent prolactin gene activation. In support of this notion, we showed that estrogen-induced regulation of ER.Pit-1 complex formation could be transferred from cell lysates prepared from estrogen-treated PR1 cells to control cell lysates. This is not true for GH3 cells; instead, direct administration of estrogen to GH3 cell lysates readily abolished ER.Pit-1 protein complex formation in a dose-dependent manner, and such estrogen-induced regulation was blocked by the antiestrogen ICI 182,780. These findings thus indicate that 1) interaction between ER and Pit-1 proteins is estrogen-regulated in ways specific to different cell types, and 2) auxiliary protein factor synthesis may be involved in this process.

Animals↗
PubMed2000

The LIM/homeodomain protein islet-1 modulates estrogen receptor functions.

LIM/Homeodomain (HD) proteins are classically considered as major transcriptional regulators which, in cooperation with other transcription factors, play critical roles in the developing nervous system. Among LIM/HD proteins, Islet-1 (ISL1) is the earliest known marker of motoneuron differentiation and has been extensively studied in this context. However, ISL1 expression is not restricted to developing motoneurons. In both embryonic and adult central nervous system of rodent and fish, ISL1 is found in discrete brain areas known to express the estrogen receptor (ER). These observations led us to postulate the possible involvement of ISL1 in the control of brain functions by steroid hormones. Dual immunohistochemistry for ISL1 and ER provided evidence for ISL1-ER coexpression by the same neuronal subpopulation within the rat hypothalamic arcuate nucleus. The relationship between ER and ISL1 was further analyzed at the molecular level and we could show that 1) ISL1 directly interacts in vivo and in vitro with the rat ER, as well as with various other nuclear receptors; 2) ISL1-ER interaction is mediated, at least in part, by the ligand binding domain of ER and is significantly strengthened by estradiol; 3) as a consequence, ISL1 prevents ER dimerization in solution, thus leading to a strong and specific inhibition of ER DNA binding activity; 4) ISL1, via its N-terminal LIM domains, specifically inhibits the ER-driven transcriptional activation in some promoter contexts, while ER can serve as a coactivator for ISL1 in other promoter contexts. Taken together, these data suggest that ISL1-ER cross-talk could differentially regulate the expression of ER and ISL1 target genes.

Animals↗
PubMed2002

Response element sequence modulates estrogen receptor alpha and beta affinity and activity.

The relationship between estrogen receptor (ER)-estrogen response element (ERE) binding affinity and estradiol (E(2))-induced transcription has not been systematically or quantitatively tested. We examined the influence of ERE palindrome length and the 3' ERE flanking sequence on ERalpha and ERbeta affinity binding in vitro and on the induction of reporter gene activity in transfected cells. The addition of one nucleotide in each arm of the 13 bp ERE palindrome, forming a 15 bp ERE palindrome, increased ERalpha and ERbeta affinity and transcription. In contrast, the addition of an AT-rich flanking sequence from genes highly stimulated by E(2) had little effect on affinity or reporter gene activity. Notable differences between ERalpha and ERbeta include: both K(d) and transcriptional induction were generally higher for ERalpha than ERbeta, better correlation between ERE palindrome length and transcriptional induction for ERalpha than ERbeta, and a better correlation between (ER-ERE)K(d) and transcriptional induction for ERalpha than for ERbeta.

Animals↗
PubMed1999

[Raloxifene: a selective modulator of estrogen receptors].

It has been demonstrated that postmenopausal hypoestrogenia induces numerous complications including osteoporosis and increased risk of cardiovascular disease. Oral or transdermal administration of estrogens can reduce these risks, but induces adverse effects. Recently, raloxifene, a new molecule from the benzothiophene family, has been demonstrated to prevent postmenopausal bone loss. It does not induce endometrial stimulation, and recent studies show that it could reduce breast cancer incidence. Its mode of action, consisting of mixed agonist and antagonistic estrogenic actions on different organs and systems, allows to classify it into the selective estrogen receptor modulator (SERM) family. In this review article, we will describe the characteristics of the molecule, its mode of action and the potential indications of its clinical use.

Breast Neoplasms↗
PubMed2005

Anti-estrogenic effects of conjugated linoleic acid through modulation of estrogen receptor phosphorylation.

We previously showed that conjugated linoleic acids (CLA) can inhibit transcriptional activation mediated by estrogen response elements (EREs) and that this activity can, at least in part, account for the reported anti-tumor effects of these compounds on breast cancer cells. Using estrogen receptor positive (ER+) MCF-7 cells, we now demonstrate that CLA inhibited both the transactivation of artificial reporter constructs driven by canonical EREs, and the expression of endogenous progesterone receptors, a gene which is transcriptionally regulated by estrogen through novel ER-binding sites. This inhibition was accompanied by downregulation of ER alpha expression and decreased ER alpha-ERE binding activity. These effects on ER alpha were not causally linked since transfection of an ER alpha expression plasmid in MCF-7 cells failed to antagonize CLA downregulation of ER alpha-ERE binding. Immunoprecipitation/Western blot studies revealed that CLA dose-dependently suppressed the degree of phosphorylation of ER alpha, a modification known to inhibit receptor-ERE interactions. As a mechanism that may account for this induced dephosphorylation of ER alpha in MCF-7, we found that CLA specifically stimulated protein phosphatase 2A (PP2A) activity. Experiments using the PP2A inhibitor okadaic acid (OA) showed that OA antagonized both the dephosphorylation effects of CLA on ER alpha and its inhibition of ER alpha-ERE binding. These results provide evidence that the anti-estrogenic activity of CLA is caused by inducing the dephosphorylation of ER alpha through stimulation of PP2A activity.

Breast Neoplasms↗
PubMed2003

Modulation of estrogen receptor activity by selective coregulators.

The estrogen receptor (ER), a member of the nuclear hormone receptor superfamily, is a hormone-regulated transcription factor that mediates the effects of estrogens and antiestrogens in breast cancer and other estrogen target cells. Because of the role of estrogens in promoting the growth and progression of breast cancer, there is great interest in exploring ways to functionally inactivate the ER, thereby suppressing ER-mediated gene expression and cell proliferation. These approaches have involved the use of antiestrogens such as tamoxifen, dominant negative ERs and, more recently, the use of corepressors. Through the use of two-hybrid screening, we have recently identified a selective repressor of estrogen receptor activity (REA). This protein is recruited to the hormone-occupied ER and selectively represses its transcriptional activity but not the other steroid and non-steroid nuclear receptors. REA also interacts with a protein, prothymosin-alpha (PTalpha), that selectively enhances ER transcriptional activity by recruiting the repressive REA protein away from ER. Analysis of the mechanisms underlying the activities of these two proteins highlights a new role for REA and PTalpha as activity-modulating proteins that confer receptor specificity.

Breast Neoplasms↗