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)

Prior studies have shown that the estrogen receptor (ER) gene is down-regulated in prostate cancer, but the mechanism of its inactivation is not known. We hypothesize that inactivation of the ER gene in prostate cancer is through promoter methylation. To test this hypothesis, we investigated the methylation status of the ER gene in prostate cancer cell lines, prostate cancer, and benign prostatic hyperplasia (BPH) tissues samples using the bisulfite genomic sequencing method. Our results show that the ER gene promoter was methylated in 100% (six of six) of the prostate cancer cell lines tested and all were accompanied by loss of ER mRNA expression. Treatment of these cell lines with demethylating agent 5-aza-2'-deoxycytidine restored ER mRNA expression in all of the ER-negative cell lines. In addition, elevated expression of DNA methyltransferase mRNA was found in all of the prostate cancer cell lines. Of the prostate tissue samples analyzed, 60% (6 of 10) in the BPH samples, 80% (8 of 10) in the low-grade cancer samples (grades I and II), and 95% (20 of 21) in the high-grade cancer samples (grades III-V) exhibited promoter methylation of the ER gene. The overall methylation levels in the cancer samples were higher than that in the BPH samples. The differences between the high-grade cancer samples and BPH samples were significant at all CpG sites. Only at three CpG sites were the differences significant between the low-grade cancer samples and BPH samples. This study presents the first evidence that ER gene is transcriptionally inactivated by DNA methylation in prostate cancer. Our data suggest that ER may be involved in the pathogenesis of prostate cancer, as well as BPH.
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PMID:Frequent methylation of estrogen receptor in prostate cancer: correlation with tumor progression. 1067 56

The discovery of a second estrogen receptor (ER), ERbeta, has led to a complete change in our views on estrogen action. The previous dogmatic view that ERalpha represented the only estrogen receptor led to a static and simplistic concept of mechanisms of estrogen action with conceptual limitations in the development of novel estrogenic and antiestrogenic drugs. It is now realized that estrogen signaling represents a complex and multi facetted signal transduction pathway with, at least in many cases, quite different roles of ERalpha and ERbeta. For instance, the two receptors appear to behave quite differently on AP1, antioxidant and Sp1-response elements where ERbeta mediates positive regulation by antiestrogens whereas ERalpha is silent under these conditions. ERalpha and ERbeta also appear to be differentially distributed in the body and within tissues. They are regulated differently and seem to have distinct biological roles, at least in certain contexts. Data are currently rapidly generated with respect to these issues from knockout animals with either of the two receptors deleted. Also double knockouts have been generated and apparently survive. ERbeta may well have significant roles in the etiology of the following diseases and symptoms: prostate cancer, osteoporosis, depression, as well as urinary incontinence in postmenopausal women. Attempts are ongoing in several labs to develop specific ligands to the two receptors. Such ligands may well turn out to be extremely important in treating the mentioned diseases and symptoms as well as possibly others.
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PMID:An update on estrogen receptors. 1070 63

The aim of the current study is to demonstrate normal and malignant prostatic epithelial cells (PrECs) as targets for receptor-mediated estrogenic and antiestrogenic action. Using an improved protocol, we have successfully isolated and maintained highly enriched populations of normal PrECs from ultrasound-guided peripheral zone biopsies, individually determined to be morphologically normal. Semiquantitative reverse transcription-PCR analyses were used to determine whether transcripts of estrogen receptor (ER)-alpha and those of ER-beta were expressed in our normal PrEC primary cultures, in a commercially available PrEC preparation (PrEC; Clontech), in an immortalized PrEC line established from a benign prostatic hyperplasia specimen (BPH-1), and in three prostatic cancer cell lines (LNCaP, PC-3, and DU145). Expression levels of ER-alpha and ER-beta transcripts were related to those of two estrogen-responsive genes [progesterone receptor (PR) and pS2], at the message levels, to gain insights into the functionality of the ER subtypes in PrECs. Interestingly, only transcripts of ER-beta, but not those of ER-alpha, were found in our primary cultures of normal PrECs, along with both PR and pS2 mRNA. These data strongly suggest that estrogen action was signaled exclusively via ER-beta in normal human PrECs. In contrast, PrEC (Clontech) and BPH-1 cells expressed both ER-alpha and ER-beta transcripts and no PR nor pS2 mRNA in PrEC and only a minimal level of PR mRNA in BPH-1. Among the three prostate cancer cell lines, LNCaP expressed ER-beta mRNA along with transcripts of PR and pS2, DU145 expressed messages of ER-beta and PR, and PC-3 cells exhibited ER-alpha, ER-beta, and pS2 mRNA. Thus, unlike normal PrECs, expression patterns of these genes in malignant PrECs are more variable. Treatment of prostate cancer cells with demethylation agents effectively reactivated the expression of ER-alpha mRNA in LNCaP and DU145 and that of pS2 message in DU145. These findings provide experimental evidence that ER-alpha gene silencing in prostate cancer cells, and perhaps also in normal PrECs, are caused by DNA hypermethylation. To evaluate the potential of using antiestrogens as prostate cancer therapies, we have assessed the growth-inhibitory action of estrogens (estradiol and diethylstilbestrol) and antiestrogens (4-hydroxy-tamoxifen and ICI-182,780) on PC-3 and DU-145 cells. In PC-3 cells, which express both ER subtypes, estrogens as well as antiestrogens are effective inhibitors. In contrast, in DU145 cells, which express only ER-beta, antiestrogens, but not estrogens, are growth inhibitors. By comparison, ICI 182,780 is the more effective cell growth inhibitor. Importantly, the ICI 182,780-induced antiproliferative effects were reversed by cotreatment of DU145 cells with an ER-beta antisense oligonucleotide, hence lending additional support to a central role played by ER-beta in mediating growth-inhibitory action of antiestrogens.
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PMID:Expression of estrogen receptor (ER)-alpha and ER-beta in normal and malignant prostatic epithelial cells: regulation by methylation and involvement in growth regulation. 1086 8

Complete estrogen blockade has long been sought as a more effective means of controlling breast cancer compared with single agent endocrine therapy. This approach may be accomplished through the use of agents which reduce estrogen production combined with agents that prevent the activity of estrogen at the cellular level. For prostate cancer, another hormonally responsive malignancy, this approach has not been successful at improving survival compared with that achieved with single agent therapy. Preclinical information is contradictory for many promising combinations and may not reflect the true nature of in vivo interaction between agents. For premenopausal patients with metastatic breast cancer, the combination of a luteinising hormone-releasing hormone (LHRH) agonist and tamoxifen is clearly effective, but whether the combination is more effective than either single agent is still controversial. Similar response rates and overall survival were reported with goserelin or goserelin plus tamoxifen by Jonat et al. in 1 randomised, prospective study, but the addition of tamoxifen improved time to progression. A second trial comparing buserelin plus tamoxifen with either single agent reported superior efficacy in terms of response rates, disease-free survival and overall survival with combination therapy. A meta-analysis of 4 randomised trials making similar comparisons, demonstrated significant improvement in median overall survival, progression-free survival, response rate, and duration of response with the combination of a LHRH agonist (goserelin or buserelin) and tamoxifen in premenopausal breast cancer patients with metastatic disease. For postmenopausal women with metastatic breast cancer, the addition of an aromatase inhibitor to tamoxifen has yet to be prospectively compared to single agent therapy. Use of endocrine combinations in the treatment of early stage breast cancer is under investigation. Preliminary results of some of the ongoing adjuvant therapy trials indicate that the combination of a LHRH agonist and tamoxifen may have similar efficacy to cyclophosphamide, methotrexate, and fluorouracil chemotherapy in premenopausal women with estrogen receptor-positive tumour. Addition of LHRH agonist therapy in premenopausal patients with estrogen receptor-positive tumour who had maintained the ovarian function following chemotherapy [cyclophosphamide, doxorubicin (adriamycin), fluorouracil, and tamoxifen], also led to a reduction in the risk of recurrence. These studies have identified a sub-population of patients who may benefit from the addition of combination endocrine therapy. Overall, the issue is quite complex and the data from many ongoing trials are still awaited with anticipation to further delineate the role of complete estrogen deprivation in this disease.
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PMID:Complete estrogen blockade for the treatment of metastatic and early stage breast cancer. 1087 21

Herbal therapies are commonly used by patients with cancer, despite little understanding about their clinical and biological activity. We recently demonstrated that the herbal combination PC-SPES, which contains licorice root, had potent estrogenic activity in vitro, in animals, and in patients with prostate cancer. Licochalcone-A (LA) is one flavonoid extracted from licorice root with antiparasitic and anti-tumor activity, but the effect on the human estrogen receptor and mechanism of anti-tumor activity is unknown. Recent studies demonstrated that the mechanism of cytotoxic effect by some estrogens may involve modulation of the anti-apoptotic protein bcl-2. In the present study, we determined if LA had estrogenic activity, anti-tumor activity, and modulated the apoptotic protein bcl-2 in human cell lines derived from acute leukemia, breast cancer, and prostate cancer. A yeast growth-based assay under the control of the human estrogen receptor (hER) demonstrated that LA was a phytoestrogen. A cell viability assay demonstrated that LA had anti-tumor activity in all cell lines tested and enhanced the effect of paclitaxel and vinblastine chemotherapy. LA induced apoptosis in MCF-7 and HL-60 cell lines, as demonstrated by cleavage of PARP, the substrate of ICE-like proteases. Immunoblot analysis demonstrated that LA decreased the anti-apoptotic protein bcl-2 and altered the bcl-2/bax ratio in favor of apoptosis. In contrast, the parent compound chalcone or estradiol did not decrease bc1-2 expression. Therefore, these data demonstrate that LA is a phytoestrogen with anti-tumor activity and is capable of modulating bcl-2 protein expression. The modulation of bcl-2 may be dependent on specific structural differences between LA and the parent compound chalcone and independent of LA estrogenicity.
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PMID:Modulation of bcl-2 and cytotoxicity by licochalcone-A, a novel estrogenic flavonoid. 1095 39

Germline mutations of BRCA1 and BRCA2 predispose to hereditary breast, ovarian, and possibly prostate cancer, yet structural mutations in these genes are infrequent in sporadic cancer cases. To better define the involvement of these genes in sporadic cancers, we characterized expression levels of BRCA1 and BRCA2 transcripts in cancer cell lines derived from neoplasms of the ovary, prostate, and breast and compared them with those expressed in primary cultures of normal epithelial cells established from these organs. We observed upregulation of BRCA1 and/or BRCA2 expression in six of seven ovarian cancer cell lines (OVCA420, OVCA429, OVCA432, ALST, DOV13, and SKOV3) when compared with levels found in normal ovary surface epithelial cells. Furthermore, five cancerous or immortalized prostatic epithelial cell lines (BPH-1, TSU-Pr1, LNCaP, PC-3, and DU145) also expressed higher levels of BRCA1 and/or BRCA2 mRNA than did primary cultures of normal prostatic epithelial cells. In contrast, only the estrogen receptor-positive MCF-7 cell line overexpressed these messages, whereas the estrogen receptor-negative breast cancer cell lines Hs578T, MDA-MB-231, and MDA-MB-468 showed no change in expression levels when compared with normal breast epithelial cells. In addition, expanding on our recent identification of a novel BRCA2 transcript variant carrying an in-frame exon 12 deletion (BRCA2 delta 12), we report increased expression of this variant in several ovarian, prostate, and mammary cancer cell lines (OVCA420, OVCA433, ALST, DOV13, SKOV3, TSU-Pr1, DU145, and MDA-MB-468). Most notably, high levels of BRCA2 delta 12 mRNA were detected in an estrogen receptor-positive breast cancer cell line, MCF-7, and in an androgen-independent prostate cancer cell line, DU-145. Interestingly, the wild-type BRCA2 transcript was barely detectable in DU145, which could be used as a model system for future investigations on BRCA2 delta 12 function. Taken together, our data suggest disruption of BRCA1 and/or BRCA2 gene expression in certain epithelial cancer cell lines of the ovary, prostate, and breast. Because wild-type BRCA1 and BRCA2 gene products increase during cell-cycle progression and are believed to exert growth-inhibitory action, enhanced expression of these genes in cancer cells may represent a negative feedback mechanism for curbing proliferation in fast-growing cells. At present, the functionality of BRCA2 delta 12 remains elusive.
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PMID:Altered expression of BRCA1, BRCA2, and a newly identified BRCA2 exon 12 deletion variant in malignant human ovarian, prostate, and breast cancer cell lines. 1097 93

Epidemiologic and experimental studies support the hypothesis that dietary estrogens from plant sources (phytoestrogens) may play a role in the prevention of breast and prostate cancer. The molecular mechanisms for such chemopreventive effect are still unclear. We investigated the possibility that phytoestrogens may bind differentially to estrogen receptor proteins (ER[alpha] and ERss) and affect the interactions of the ligand-ER complexes with different estrogen response element (ERE) sequences. We used fluorescence polarization to measure the binding affinities of genistein, coumestrol, daidzein, glyceollin, and zearalenone for human ER[alpha] and ERss. Competition binding experiments revealed higher affinity of the phytoestrogens for ERss than for ER[alpha]. Genistein [median inhibitory concentration 12nM] is the most potent and has the same relative binding affinity for ERss as 17ss-estradiol. We also studied the effect of these phytoestrogens on the ability of ER[alpha] and ERss to associate with specific DNA sequences (EREs). The direct binding of human recombinant estrogen receptors to fluorescein-labeled EREs indicates that phytoestrogens can cause conformational changes in both human ERs, which results in altered affinities of the complexes for the ERE from the Xenopus vitellogenin A2 gene and an ERE from the human pS2 gene.
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PMID:Interactions of dietary estrogens with human estrogen receptors and the effect on estrogen receptor-estrogen response element complex formation. 1118 85

A semi-nested reverse transcriptase-polymerase chain reaction (RT-PCR) was applied to evaluate the presence of estrogen receptor-alpha (ER-alpha) in human prostate cancer cells. Unexpectedly, a novel fatty acid synthase (FAS)/ER-alpha fusion transcript was identified, in which the N-terminus of FAS was fused in-frame with the C-terminus of ER-alpha. The existence of the FAS/ER-alpha transcript was further confirmed by RT-PCR analysis using various sets of amplification primers and different reverse-transcribed primers in the presence of dimethyl sulfoxide to eliminate the secondary structure of RNA. The predicted FAS/ER-alpha protein would contain largely domain I of FAS and the entire ligand binding domain of ER-alpha. The FAS/ER-alpha was expressed in a variety of human cancer cell lines including prostate, breast, cervical and bladder cancer cell lines. Our data suggest that the presence of FAS/ER-alpha may complicate the FAS and the ER-alpha signalling pathway.
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PMID:Identification of a novel FAS/ER-alpha fusion transcript expressed in human cancer cells. 1101 65

The anti-proliferative action of the seco-steroid hormone 1alpha, 25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] extends to some, but not all breast and prostate cancer cell lines. By elucidating the molecular mechanisms mediating the sensitivity of these cells, we can identify critical target genes regulated directly or indirectly by 1alpha,25(OH)2D3 and pathways potentially disrupted during transformation. In this study, we demonstrated the induction of expression of BRCA1 mRNA and protein as well as transcriptional activation from the BRCA1-promoter by 1alpha,25(OH)2D3 in the sensitive breast cancer cell line MCF-7. This was not observed in the 1alpha,25(OH)2D3-resistant breast cancer cell line MDA-MB-436. The induction of BRCA1 mRNA was blocked by cyclohexamide. This indicated that transcriptional activation was mediated indirectly by the vitamin D receptor (VDR). Inhibition of VDR protein levels by stable transformation of the anti-sense VDR in MCF-7 reduced the sensitivity of MCF-7 to 1alpha,25(OH)2D3 by 50-fold. In addition, the induction of BRCA1 protein and transcriptional activation of a BRCA1 promoter-luciferase reporter construct was abrogated in the stable transformant with the greatest reduction of VDR levels. Examination of other breast and prostate cancer cell lines revealed that sensitivity to the anti-proliferative effects of 1alpha, 25(OH)2D3 was strongly associated with an ability to modulate BRCA1 protein. Furthermore, the expression of the estrogen receptor in these cell lines strongly correlated with their sensitivity to 1alpha,25(OH)2D3 and their ability to modulate BRCA1 expression. Taken together, our data support a model whereby the anti-proliferative effects of 1alpha,25(OH)2D3 are mediated, in part, by the induction of BRCA1 gene expression via transcriptional activation by factors induced by the VDR and that this pathway is disrupted during the development of prostate and breast cancers.
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PMID:The anti-proliferative effects of 1alpha,25(OH)2D3 on breast and prostate cancer cells are associated with induction of BRCA1 gene expression. 1104 97

A sensitive semi-nested reverse transcriptase-polymerase chain reaction (RT-PCR) amplification was performed to evaluate estrogen receptor-alpha (ER-alpha) mRNA expression in prostate cancer cell lines. We demonstrated the presence of wild-type ER-alpha (wt ER-alpha) and five ER-alpha variants, designated ER-alphaA, B, C, D, and E. Unlike ER-alphaA and D, ER-alphaB, C, and E were not previously reported in normal or cancerous mammalian cells. DNA sequencing analysis of these ER-alpha variants revealed the genetic changes to be either in-frame or out-of-frame deletions. The expression of each ER-alpha variant differs significantly depending on the androgen responsiveness, tumorigenic and metastatic potentials of each prostate cancer cell line. The potential functional significance of ER-alpha variants was assessed in yeast two-hybrid and ERE promoter-reporter mammalian transcription assay systems. The results of these studies indicated that none of the ER-alpha variants can form homo- or heterodimers either with wt ER-alpha or among themselves in vivo, and that these ER-alpha variants have no demonstrable transcriptional or dominant-negative activity, as assessed in vitro.
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PMID:Identification and characterization of estrogen receptor variants in prostate cancer cell lines. 1117 5


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