Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen receptor (ER)-beta is the predominant ER subtype in prostate cancer (PCa). We previously demonstrated that ICI 182,780 (ICI), but not estrogens, exerted dose-dependent growth inhibition on DU145 PCa cells by an ER-beta-mediated pathway. Transcriptional profiling detected a greater than three-fold upregulation of seven genes after a 12-hour exposure to 1 microM ICI. Semiquantitative reverse transcriptase polymerase chain reaction confirmed the upregulation of four genes by ICI: interleukin-12alpha chain, interleukin-8, embryonic growth/differentiation factor, and RYK tyrosine kinase. Treatment with an ER-beta antisense oligonucleotide reduced cellular ER-beta mRNA and induced loss of expression of these genes. Sequence analysis revealed the presence of consensus NFkappaB sites, but not estrogen-responsive elements, in promoters of all four genes. Reporter assay and chromatin immunoprecipitation experiments demonstrated that ICI-induced gene expression could be mediated by crosstalk between ER-beta and the NFkappaB signaling pathway, denoting a novel mechanism of ER-beta-mediated ICI action. Therefore, combined therapies targeting ER-beta and NFkappaB signaling may be synergistic as treatment for PCa.
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PMID:ICI 182,780-regulated gene expression in DU145 prostate cancer cells is mediated by estrogen receptor-beta/NFkappaB crosstalk. 1675 16

Estrogen receptor beta (ERbeta) plays a protective role against uncontrolled cell proliferation. ERbeta is lost during prostate cancer (CaP) progression suggesting its direct involvement in contrasting tumor proliferation in this disease; however, the molecular mechanism at the basis of this effect has not been clearly defined yet. Possible molecular targets of ERbeta were assessed in DU145 cells, a CaP cell line expressing only ERbeta. Cells treated from 1 to 9 days with different doses of estradiol or diarylpropionitrile (DPN, an ERbeta-selective agonist) show a time-dependent decrease in cell proliferation. The reduced proliferation rate is accompanied by the stimulation of ERbeta expression and the increase of cyclin-dependent kinase inhibitor p21. We demonstrate that the endogenous ERbeta is one of the mediator of the antiproliferative action of estrogens enhancing the synthesis of molecules such as p21 that control cell cycle, an effect amplified by the autoregulation of ERbeta expression. Our observations suggest that CaP, when expressing a functional ERbeta, might be sensitive to the antiproliferative action of estrogens; therefore, ERbeta specific agonists might be valid candidates for new pharmacological approaches to this disease.
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PMID:Estrogen receptor beta (ERbeta) and inhibition of prostate cancer cell proliferation: studies on the possible mechanism of action in DU145 cells. 1702 11

Mounting evidence supports a key role played by estrogen or estrogen in synergy with an androgen, in the pathogenesis of prostate cancer (PCa). New experimental data suggest that this process could begin as early as prenatal life. During adulthood, estrogen carcinogenicity is believed to be mediated by the combined effects of hormone-induced, unscheduled cell proliferation and bioactivation of estrogens to genotoxic carcinogens. Increased bioavailability of estrogen through age-dependent increases in conversion from androgen could also be a contributing factor. Individual variations and race-/ethnic-based differences in circulating or locally formed estrogens or in tissue estrogen responsiveness may explain differential PCa risk among individuals or different populations. Estrogen receptor (ER)-alpha and ER-beta are the main mediators of estrogen action in the prostate. However, ER-beta is the first ER subtype expressed in the fetal prostate. During cancer development, ER-beta expression is first lost as tumors progress into high grade in the primary site. Yet, its reexpression occurs in all metastatic cases of PCa. A change in cytosine methylation in a regulatory CpG island located in the proximal promoter of ER-beta may constitute an "on/off" switch for reversible regulation of ER-beta expression. A variety of estrogenic/antiestrogenic/selective estrogen receptor modulator (SERM)-like compounds have been shown to use non-ERE pathways, such as tethering of ER-beta to NF-kappaB binding proteins, Sp2, or Ap1 for gene transactivation. These findings open new avenues for drug design that now focuses on developing a new generation of estrogen-based PCa therapies with maximal proapoptotic action but few or no side effects.
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PMID:Estrogens and antiestrogens as etiological factors and therapeutics for prostate cancer. 1726 66

Prostate cancer is the most frequently diagnosed cancer and a leading cause of cancer deaths in American men. High dietary intake and status of the essential trace element selenium (Se) have been consistently correlated with reduced risk for prostate cancer. One molecular mechanism by which Se may reduce prostate cancer risk is by catalyzing disulfide bond formation or, otherwise, complexing with reactive sulfhydryl groups in transcription factors, thus altering their binding to DNA and regulation of gene expression. Estrogen plays a role in the etiology of prostate cancer. Estrogen receptors contain cysteines in zinc fingers that are susceptible to oxidation and internal disulfide bond formation, which can prevent DNA binding. We hypothesized that Se alteration of estrogen receptor (ER) binding to DNA and estrogen-regulated gene expression may be one mechanism by which it exerts its chemopreventive effects. LNCaP human prostate cancer cells were treated with 0.05 mumol/L (control) or 5.0 mumol/L (high) Se as methylseleninic acid (MSA). Electrophoretic mobility shift assays showed that binding of ER-beta to the estrogen response element was a nonsignificant 14% lower in cells treated with high MSA. Run-on transcription assays showed no significant changes in transcription rates for estrogen-regulated genes, and steady-state mRNA levels for those genes, assayed by reverse transcription-polymerase chair reaction, were likewise unaffected by MSA. These results suggest that the well-documented chemopreventive effects of Se against prostate cancer may be mediated by mechanisms other than inhibition by monomethylated Se compounds of ER-beta activation or estrogen-regulated gene expression.
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PMID:Estrogen receptor activation and estrogen-regulated gene expression are unaffected by methylseleninic acid in LNCaP prostate cancer cells. 1743 22

The role of estrogens in the etiology of prostate cancer is controversial. To demonstrate the specific effects of estrogens and androgens on the development of the prostatic epithelial hyperplasia, we used luteinizing hormone receptor knockout mice (LuRKO), which are resistant to pituitary regulation mediated by luteinizing hormone, lack postnatal androgen production, and have rudimentary accessory sex glands, the growth of which can be induced with exogenous androgen replacement. This model is thus ideal for the investigation of direct hormonal effects on the prostate. Testosterone, but not 5alpha-dihydrotestosterone, replacement from 21 days of life for 8 weeks induced pronounced hyperplasia and inflammation in the prostates of LuRKO mice. Interestingly, 5alpha-dihydrotestosterone combined with 17beta-estradiol did not induce hyperplasia or inflammation, and treatments with inhibitors of estrogen action, aromatase inhibitor, and ICI 182780 further exacerbated testosterone-induced hyperplastic growth. However, the activation of estrogen receptor (ER)-beta with a specific agonist, DPN [2,3-bis(4-hydroxyphenol)-propionitrile], prevented the development of prostatic hyperplasia and inflammation in testosterone-treated LuRKO mice. Thus, it seems that in the presence of sufficient androgenic stimulation, it is the balance between ER-alpha- and ER-beta-mediated signaling that determines whether estrogens promote hyperplasia or protect the prostate against hyperplastic changes.
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PMID:Delay of postnatal maturation sensitizes the mouse prostate to testosterone-induced pronounced hyperplasia: protective role of estrogen receptor-beta. 1764 Sep 60

In the prostate, estrogen receptor beta (ERbeta), the preferred receptor for phytoestrogens, has features of a tumor suppressor. To investigate the mechanisms underlying the beneficial effects on prostate cancer of histone deacetylase inhibitor valproic acid (VPA) and phytoestrogen tectorigenin, we analyzed the expression of ERbeta after tectorigenin or VPA treatment. For further functional analysis, we knocked down ERbeta expression by RNA interference. LNCaP prostate cancer cells were treated with 5 mmol/L VPA or 100 micromol/L tectorigenin and transfected with small interfering RNA (siRNA) against ERbeta. Control transfections were done with luciferase (LUC) siRNA. Expression of ERbeta was assessed by Western blot. mRNA expression was quantitated by real-time reverse transcription-PCR. Expression of ERbeta mRNA and protein markedly increased after VPA or tectorigenin treatment. When ERbeta was knocked down by siRNA, the expression of prostate-derived Ets factor, prostate-specific antigen, prostate cancer-specific indicator gene DD3(PCA3), insulin-like growth factor-1 receptor, the catalytic subunit of the telomerase, and ERalpha was up-regulated and the tectorigenin effects were abrogated. ERbeta levels were diminished in prostate cancer and loss of ERbeta was associated with proliferation. Here, we show that siRNA-mediated knockdown of ERbeta increases the expression of genes highly relevant to tumor cell proliferation. In addition, we show that one prominent result of treatment with VPA or tectorigenin is the up-regulation of ERbeta resulting in antiproliferative effects. Thus, these drugs, by restoring the regulatory function of ERbeta in tumor cells, could become useful in the intervention of prostate cancer.
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PMID:The relevance of estrogen receptor-beta expression to the antiproliferative effects observed with histone deacetylase inhibitors and phytoestrogens in prostate cancer treatment. 1791 55

Androgens have long been known to be the major sex hormones that target the prostate during development, maturation, and carcinogenesis. It is now apparent that estrogens, both those synthesized by the body as well as those from our environment, also target the prostate during all stages of development. Little is known about the mechanisms involved in estrogen stimulation of carcinogenesis and less is known about how to prevent or treat prostate cancer through estrogenic pathways. To better understand how estrogens mediate their carcinogenic effects, the respective roles of estrogen receptor (ER)-alpha and ER-beta must be elucidated in the epithelial and stromal cells that constitute the prostate. Lastly, the significance of ER signaling during various ontogenic periods must be determined. Answers to these questions will further our understanding of the mechanisms of estrogen/ER signaling and will serve as a basis for chemopreventive and/or chemotherapeutic strategies for prostate cancer.
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PMID:Steroid hormones and carcinogenesis of the prostate: the role of estrogens. 1792 63

Exposure to exogenous (oral contraceptives, postmenopausal hormone therapy) and endogenous (number of ovulatory cycles, adiposity) steroid hormones is associated with breast cancer risk. Breast cancer risk associated with these exposures could hypothetically be modified by genes in the steroid hormone synthesis, metabolism and signaling pathways. Estrogen receptors are the first step along the path of signaling cell growth and development upon stimulation with estrogens. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium has systematically selected haplotype tagging SNPs in genes along the steroid hormone synthesis, metabolism and binding pathways, including the estrogen receptor beta (ESR2) gene. Four htSNPs tag the 6 major (>5% frequency) haplotypes of the ESR2 gene. These polymorphisms have been genotyped in 5,789 breast cancer cases and 7,761 controls nested within the American Cancer Society Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study and Women's Health Study cohorts. None of the SNPs were independently associated with breast cancer risk. One haplotype of the ESR2 gene was associated with breast cancer risk before correction for multiple testing (OR 1.17, 95% CI 1.07-1.28, p = 0.0007). This haplotype remained associated with breast cancer risk after adjustment for multiple testing using a permutation procedure. There was no statistically significant heterogeneity in SNP or haplotype odds ratios across cohorts. These data suggest that inherited variants in ESR2 (while possibly conferring a small increased risk of breast cancer) are not associated with appreciable (OR > 1.2) changes in breast cancer risk among Caucasian women.
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PMID:Haplotypes of the estrogen receptor beta gene and breast cancer risk. 1793 38

It was recently demonstrated that antiestrogens prevented prostate cancer (PRCA) in men. The source of estradiol (E2) that contributes to carcinogenesis, as well as the selected estrogen receptor (ER) signaling pathway, is unknown. To evaluate estrogen's effects in carcinogenesis, we developed a new model of PRCA utilizing testosterone and E2 to stimulate PRCA. To determine whether local in situ production of E2 affected incidence of PRCA, aromatase-knockout (ArKO) mice were evaluated. In contrast to the wild-type mice, ArKO mice had reduced incidences of PRCA, which implicates in situ production of E2 as an important determinant of PRCA. To determine whether E2-mediated responses were due to ER alpha or ER beta signaling, ER alpha-knockout (alphaERKO) or ERbeta-knockout (betaERKO) mice were used. Prostates from betaERKO mice underwent biochemical and histological carcinogenesis similar to wild-type mice, whereas prostates from alphaERKO mice remained free of pathology. These data suggest that effective prevention of carcinogenesis will require antagonism of ER alpha but not ER beta. This mouse model provides a means to examine genetic gain and loss of function and determine the efficacy of therapeutics on prostatic carcinogenesis.
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PMID:Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling. 1940 47

Different polymorphisms have been described in steroid hormone receptors which are related with variable human diseases. Polymorphisms of estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) are related not only with reproductive diseases, but also with osteoporosis, cardiovascular disease, malignancy such as breast cancer, and disorders involving central nervous system. They are also related with individual reactivity to medications. Polymorphisms of androgen receptor are known to be associated with prostate cancer. Polymorphisms of glucocorticoid receptor are related with severity of inflammation and allergy. Analysis of steroid hormone receptor polymorphisms will make it possible to develop tailored medicine for human diseases.
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PMID:[Polymorphisms of steroid hormone receptors]. 1819 42


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