UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Forty years ago, Lerner and coworkers (1958) discovered the first nonsteroidal antiestrogen and Jensen (Jensen and Jacobson, 1960) identified a target for drug action, the ER. This knowledge opened the door for the clinical development of tamoxifen which we now know provides a survival advantage in both node-positive and node-negative patients with ER-positive disease (Early Breast Cancer Trialists Collaborative Group, 1992, 1998). The drug has been studied extensively, and the results have provided an invaluable insight into possible ancillary advantages of "antiestrogens", i.e., maintenance of bone density and the prevention of coronary heart disease, and possible disadvantages, i.e., rat liver carcinogenesis and an increased risk of endometrial cancer. Most importantly, the identification of the target site-specific actions of tamoxifen caused a paradigm shift in the prospective uses of antiestrogens from a direct exploitation of the antitumor properties to the broader application as a preventative for osteoporosis, but with the beneficial side effects of preventing breast and endometrial cancer. Raloxifene, a second-generation SERM, has all the properties in the laboratory that would encourage development as a safe preventative for osteoporosis (Jordan et al., 1997). As a result, raloxifene has been evaluated in more than 11,000 postmenopausal women and found to maintain bone density with significant decreases in breast cancer incidence and no increase in endometrial thickness. Raloxifene is now available as a preventative for osteoporosis in postmenopausal women. There is every reason to believe that a multifaceted agent like raloxifene will find widespread use, and there will be continuing interest by the pharmaceutical industry in the development of new agents with even broader applications. The extensive clinical effort is augmented by past molecular innovations in the laboratory and the future promise of new discoveries. The cloning and sequencing of the ER (Green et al., 1986; Greene et al., 1986) has allowed the development of an ER knock-out mouse (Lubahn et al., 1993) that compliments Jensen's pioneering work (Jensen and Jacobson, 1962) and describes the consequences of the loss of ER alpha. However, ER beta (Kuiper et al., 1996), the second ER, has provided an additional dimension to the description of estrogen and antiestrogen action. For the future, the development of ER beta monoclonal antibodies, the classification of target sites for the protein around the body, and the creation of ER beta and ER alpha, beta knock-out mice will identify new therapeutic targets to modulate physiological functions. Clearly, the successful crystallization of ER alpha with raloxifene (Brzozowski et al., 1997) must act as a stimulus for the crystallization of ER beta. The central issue for research on antiestrogen pharmacology is the discovery of the mechanism (or mechanisms) of target site-specificity for the modulation of estrogenic and antiestrogenic response. The description of a stimulatory pathway for antiestrogens through an AP-1 ER beta signal transduction pathway (Paech et al., 1997), although interesting, may not entirely explain the estrogenicity of antiestrogens. The model must encompass the sum of pharmacological consequences of signal transduction through ER alpha and ER beta with the simultaneous competition from endogenous estrogens at both sites. This is complicated because estradiol is an antagonist at ER beta through AP-1 sites (Paech et al., 1997), so this is clearly not the pathway for estrogen-induced bone maintenance in women. Estrogen is stimulatory through ER alpha, but antiestrogens are usually partial agonists and may either block or stimulate genes. However, we suggest that the ER alpha stimulatory pathway could be amplified through selective increases in coactivators. The principle is illustrated with the MDA-MB-231 cells stably transfected with the cDNAs for the wild-type and the amino acid 351 mutan
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PMID:Basic guide to the mechanisms of antiestrogen action. 964 65

Although estrogen receptor (ER)-alpha is expressed in both benign and malignant ovarian tumors, the role of ER in ovarian carcinogenesis of epithelial tumors is still unknown. In view of the recent characterization of ER-beta, a second form of ER that seems to be highly expressed in ovaries, we reexamined this issue by studying the relative expression of ER-alpha and -beta in human ovarian tumor progression. We developed a competitive PCR assay based on coamplification of the two ERs in target nucleotide sequences displaying a high homology (exons 3 and 4). Coamplification experiments with varying amounts of plasmids containing ER-alpha and -beta cDNAs showed that this assay was reliable for discriminating as little as a 2-fold difference in the initial ER-alpha:ER-beta cDNA ratio. The relative expression of ER-alpha compared with ER-beta mRNAs was studied in human ovarian cancer cell lines (n = 5) and in normal ovaries (n = 6), then in human benign and malignant tumor samples including ovarian cysts (n = 24), borderline tumors (n = 3), and cancers (n = 10). In normal ovaries, ER-beta mRNA was the predominant ER form, whereas in ovarian cancer cell lines ER-alpha mRNA was markedly increased as compared with ER-beta. In benign and borderline tumors, ER-beta mRNA was detected in 78% of tumors, whereas ER-alpha mRNA was detected in 29%. In ovarian carcinomas, both ER-alpha and -beta mRNAs were expressed in 80% of tumors. The ER-alpha:ER-beta mRNA ratio was >1 in only one cyst sample (4%). In contrast, the ER-alpha:ER-beta mRNA ratio was markedly increased in ovarian cancers because 60% showed an ER-alpha:ER-beta mRNA >1. In situ hybridization experiments showed overlapping tissular distribution of ER-beta and -alpha expression in cancers and cysts, with a main localization in the epithelium and only a low level of expression in stromal cells. In summary, we found an increase in the ER-alpha:ER-beta mRNA ratio in ovarian carcinomas as compared with normal ovaries and cysts. These data suggest that overexpression of ER-alpha relative to ER-beta mRNA may be a marker of ovarian carcinogenesis.
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PMID:Differential expression of estrogen receptor-alpha and -beta messenger RNAs as a potential marker of ovarian carcinogenesis. 985 67

The role of estrogens in breast and other cancers has been extensively investigated for many years, and historically most of these studies have focused on the hormonal regulation of cell proliferation. The most recent work in this area has focused on the expression of genes likely to mediate proliferation (e.g., growth factors, proto-oncogenes, etc.) and their regulation by the classic nuclear estrogen receptor, ER-alpha. In this chapter, we present a synopsis of several new developments in this area of ER-regulated gene expression. These developments include the following: 1) the selective activation of ER domains by partial estrogen antagonists, such as tamoxifen and other ligands; 2) the effects of ER-alpha overexpression and gene knockout on the development of breast and uterine cancers in experimental animal models; 3) mechanisms by which steroid hormones regulate programmed cell death, cell cycle progression, cell-substratum interactions, and genomic instability in cancer cells; 4) identification of nuclear proteins that interact with the ER in the presence of agonists and antagonists, the effect of ligand binding on the receptor structure, and the interactions of liganded and nonliganded receptors with coactivators, corepressors, and other regulatory proteins; and 5) the biochemical properties, cellular distribution, and potential biologic roles for the newly discovered ER-beta. Although there is an increasing interest in understanding the role of estrogens as endogenous carcinogens, it remains clear that ER-mediated regulation of gene expression plays many significant roles in normal and cancer cells, and increased knowledge of the mechanisms involved will improve our overall understanding of hormonal carcinogenesis.
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PMID:Estrogen receptor-mediated processes in normal and cancer cells. 1096 25

We have carried out a quantitative analysis of ER-alpha and ER-beta mRNA expression in normal (n = 11) and breast cancer (n = 112) tissues using a real-time (Taq-Man) PCR assay. Expression of ER-beta mRNA variants has also been studied by triple-primer PCR assay. ER-alpha mRNA levels in normal breast tissues were significantly (p < 0.01) lower than those in ER-positive breast cancers but not significantly different from those in ER-negative breast cancers. However, ER-beta mRNA levels in normal breast tissues were significantly (p < 0.01) higher than those in ER-positive and ER-negative breast cancers. Proportions of ER-beta1 and ER-beta2 mRNA expression among total ER-beta mRNA expression were significantly higher and those of ER-beta5 and ER-beta5; mRNA were significantly lower in normal breast tissues than in ER-positive and ER-negative breast cancers. ER-beta mRNA levels and proportions of ER-beta mRNA variants did not show any significant correlation with age, tumor size, lymph node status and histological grade. Our results demonstrate that ER-alpha mRNA is up-regulated and ER-beta mRNA is down-regulated during carcinogenesis of breast cancers. Changes in proportions of ER-beta mRNA variants are also implicated in this process.
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PMID:Quantitative analysis of estrogen receptor-beta mRNA and its variants in human breast cancers. 1107 41

To understand the significance of estrogen receptor beta (ERbeta) in mammary carcinogenesis, we evaluated the expression of ERbeta in preinvasive mammary tumors. The percentage of ERbeta-positive epithelial or tumoral cells was assayed by quantitative immunohistochemistry using an image analyzer in 130 lesions of varying histological risk from 118 patients [71 with benign breast disease (BBD) and 59 with carcinoma in situ (CIS)] and compared with 118 adjacent histologically normal glands. Five groups of lesions with an increasing risk of invasive cancer, from BBD without hyperplasia to high-grade CIS, were studied. Results were compared with ERalpha and Ki67 immunostaining. The percentage of ERbeta-positive cells was high (median, 85%) in "normal" mammary glands and in nonproliferative BBD and decreased significantly (P < 0.0001) in proliferative BBD without atypia and in CIS, contrasting with an inverse progression for the ERalpha level. In normal mammary glands, the ERbeta level did not vary according to the nature of the lesion at the periphery and was significantly higher (P < 0.007) than in adjacent preinvasive lesions, except in nonproliferative BBD. The ERbeta level decreased in proliferative BBD, anticipating the ERalpha increase, which was significant in BBD with atypia. In high-grade ductal carcinoma in situ, both ER levels were low. The ratio between ERbeta and ERalpha was high in normal glands, and decreased significantly in proliferative lesions. ERbeta staining was inversely correlated with Ki67 (r = -0.333; P < 0.001), more particularly in high-grade ductal carcinoma in situ (r = -0.57; P < 0.02). The marked and early decreased level of ERbeta protein associated with other criteria of cell proliferation suggests a protective effect of ERbeta against the mitogenic activity of estrogens in mammary premalignant lesions. Knowledge of the ERbeta and ERalpha content in each preinvasive lesion should help to rationalize antiestrogen preventive therapy adapted to each individual patient.
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PMID:Decreased expression of estrogen receptor beta protein in proliferative preinvasive mammary tumors. 1128 27

Recent studies indicate that the expression of ER beta in breast cancer is lower than in the normal breast, suggesting that ER beta could play an important role in carcinogenesis. To investigate this hypothesis, we engineered ER-negative MDA-MB-231 (human breast cancer cells) to reintroduce either ER alpha or ER beta protein with an adenoviral vector. In these cells, ER beta (as ER alpha) expression was monitored using RT-PCR and Western blot. ER beta protein was localized in the nucleus (immunocytochemistry) and able to transactivate estrogen-responsive reporter constructs in the presence of E2. ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression. The pure antiestrogen ICI 164, 384 completely blocked ER alpha and ER beta estrogen-induced activities. ER beta inhibited MDA-MB-231 cell proliferation in a ligand-independent manner, whereas ER alpha inhibition of proliferation is hormone dependent. Moreover, ER beta and ER alpha decreased cell motility and invasion. Our data bring the first evidence that ER beta is an important modulator of proliferation and invasion of breast cancer cells and support the hypothesis that the loss of ER beta expression could be one of the events leading to the development of breast cancer.
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PMID:ER beta inhibits proliferation and invasion of breast cancer cells. 1151 91

Short- and long-term experiments were designed to determine the effects of toremifene (TOR) on estrogen-related endometrial carcinogenesis in mice. In the short-term experiment, a single low dose of TOR (0.2 mg / 30 g body weight) decreased expression of c-fos, interleukin (IL)-1alpha, estrogen receptor (ER)-alpha mRNAs and corresponding proteins induced by estradiol-17beta (E(2)), in the uteri of the ovariectomized mice. Expression of ER-beta mRNA was increased by the TOR treatment, compared with the control. In the long-term experiment, 106 female ICR mice were given N-methyl-N-nitrosourea (MNU) into their uterine corpora. The animals were divided into four groups as follows: group 1, E(2) diet (5 ppm) plus TOR (0.2 mg / 30 g body weight, subcutaneously, every four weeks); group 2, E(2) diet alone; group 3, basal diet plus TOR. Group 4 served as the control. TOR treatment decreased the incidence of MNU and E(2)-induced endometrial adenocarcinoma and atypical hyperplasia at the termination of the experiment (30 weeks after the start). These results suggest that TOR exerts preventive effects against estrogen-related endometrial carcinogenesis in mice, through the suppression of c-fos as well as IL-1alpha expression induced by E(2). Such suppressive effects of TOR may be related to the decreased ER-alpha and increased ER-beta expressions.
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PMID:Inhibitory effects of toremifene on N-methyl-N-nitrosourea and estradiol-17beta-induced endometrial carcinogenesis in mice. 1207 10

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous pollutant and promoter of carcinogenesis. This study investigated the interaction between TCDD and different estrogens in a cancer cell line (ID8) derived from mouse ovarian epithelium. TCDD-induced ethoxyresorufin-O-deethylase (EROD) activity and cytochrome P4501A1 (CYP1A1) expression in a dose- and time-dependent manner. Estrogen receptor (ER) alpha mRNAs were constitutively expressed, but ER beta and progesterone receptor (PR) mRNAs were not expressed. Induction of EROD by TCDD was completely inhibited by a alpha-naphthoflavone and phenanthroline, two aryl hydrocarbon receptor (AhR) antagonists. Progesterone and gonadotropins (FSH and LH) had no effect on the induction of EROD by TCDD. Congeners of 17beta-estradiol (E2) increased the induction of EROD activity by TCDD dose-dependently in the relative potency order: estrone (El)>E2> or = 4-hydroxyestradiol (4OHE2)> or = 2-hydroxyestradiol (2OHE2). In contrast, estriol (E3) decreased EROD activity induced by TCDD. E2 increased TCDD-induced CYP1A1 protein and mRNA whereas E3 decreased both the protein and mRNA. E2 did not alter luciferase activity induced by TCDD in cells transfected with a luciferase reporter containing dioxin response elements (DRE) or a CYP1A1 promoter. In contrast, E3 dose-dependently decreased the luciferase activity. A pure anti-estrogen (ICI 182780) inhibited the interaction between E2 and TCDD but did not block E3's effect on EROD activity. These results indicate that E2 may affect TCDD-induced CYP1A1 expression by a mechanism different from E3 in ID8 cells. It appears that the potentiation of E2 in the induction of CYP1A1 by TCDD occurs by a mechanism involving ER alpha since a specific ER antagonist blocked the potentiation. The inhibitory effect of E3 may be due to a rapid direct effect on EROD and a later suppression of CYP1A1 expression.
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PMID:Estradiol enhances and estriol inhibits the expression of CYP1A1 induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in a mouse ovarian cancer cell line. 1209 19

Epidemiological studies have indicated that females may be at greater risk of smoking associated lung cancer compared with males. Several lines of biochemical evidence support these observations. A possible role of circulating steroid hormones in the etiology of lung cancer has been hypothesized. In the present paper, we have studied the expression of the estrogen receptors (ER)-alpha and ER beta in histologically normal human lung tissue and lung tumor cell lines. Relative ER mRNA levels were measured by reverse transcriptase-PCR and normalized to the level of expression of the glyceraldehyde 3-phosphate dehydrogenase gene (GAPDH). In lung tissue, an ER alpha transcript was found at various levels in 38 out of 46 cases (83%). ER beta was expressed in all cases. The ERs were expressed at similar levels in females and males, and the levels of ER alpha and ER beta mRNA were significantly related (P<0.0001). Compared with the lung tissue, ER expression levels were lower in 16 human lung tumor cell lines and two immortalized human bronchial epithelial cell lines. Five of the tumor cell lines (31%) expressed detectable levels of ER alpha and both of the immortalized cell lines showed a weak ER alpha expression level. All cell lines expressed the ER beta. The lung cell lines BEAS-2B and DB354 showed significantly reduced cell proliferation in response to tamoxifen and a minor increased growth in response to 17 beta-estradiol. In conclusion, ER genes are abundantly expressed in both histologically normal human lung and lung tumor cell lines. This indicates a possible role of ERs in lung carcinogenesis.
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PMID:Expression of estrogen receptors alpha and beta in human lung tissue and cell lines. 1214 Jan 38

Steroid hormones and their receptors play critical roles in the growth, development, and maintenance of the male reproductive tract. Genistein, a naturally occurring isoflavonoid primarily found in soybeans, interacts with estrogen receptors alpha and beta (ER alpha and beta), with preferential affinity for ER beta. This is one mechanism whereby genistein may affect growth and development and potentially alter susceptibility to carcinogenesis. Previous studies have indicated effects of soy and/or genistein in the male rodent reproductive tract under certain exposure conditions. The current study was undertaken to determine if modulation of the expression of ER alpha and ER beta by dietary genistein may contribute to those effects. Rats in a two-generation study were fed 0, 5, 100, or 500 ppm genistein prior to mating and through pregnancy and lactation. At weaning, male pups were selected in each of the F(1) and F(2) generations and half of the pups continued on the same diet as their dams (G/G, continuous exposure) while their litter mates were placed on control chow (G/C, gestational and lactational exposure) until sacrifice on PND 140. Male reproductive organ weights, serum levels of testosterone and dihydrotestosterone (DHT), and ER alpha and ER beta protein levels in the ventral and dorsolateral prostate were the endpoints measured. Prostate sections were also evaluated microscopically. Statistically significant elevations in testosterone and DHT were observed in PND 140 animals from the F(1) generation, but they were not accompanied by organ weight changes. Body weight in the continuously dosed 500 ppm F(1) PND 140 animals was depressed relative to control, but organ weights in animals of either generation showed few treatment-related effects. While estrogen receptor levels were quite variable, levels of ER beta in the dorsolateral prostate were significantly depressed in all dose groups in the G/C exposure and the high dose group of the G/G exposure in F(1) rats, but not in F(2) rats. Given the growing body of knowledge on the significance of ER beta in the prostate, the evidence for apparent down regulation of this receptor by genistein may have implications for reproductive toxicity and carcinogenesis that warrant further investigation.
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PMID:Estrogen receptor expression in the prostate of rats treated with dietary genistein. 1227 Feb 17

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