Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04155 (pS2)
 1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In view of the limitations associated with the present tumor markers for prostate cancer, we have examined the potential expression of two further markers, Cathepsin-D and pS2, in human prostate and attempted to link their concentrations with the histopathology of the tissue, the PSA levels and the androgenic status of the gland. Cathepsin-D and pS2 were measured in cytosol fractions obtained from 22 patients with benign prostatic hyperplasia (BPH) and 20 patients with prostate cancer (CaP) employing immunoassays specific for these markers. The concentrations of Cathepsin-D (BPH: mean +/- SEM = 18.50 +/- 1.88 nmol/g protein; CaP = 19.75 +/- 2.49 nmol/g protein) and pS2 (BPH = 1,024.7 +/- 348.06 ng/g protein; CaP = 1,513.88 +/- 268.60 ng/g protein) were not different in the two tissue types, whereas PSA in BPH tissue (1,952.27 +/- 249.93 micrograms/g protein) was significantly higher than the measurements in CaP (583.75 +/- 104.33 micrograms/g protein). However, none of the tumor marker concentrations correlated with the degree of differentiation of the tumors, and we were unable to establish any correlation with the levels of testosterone and dihydrotestosterone in the tissue. In conclusion, although Cathepsin-D and pS2 are expressed in prostate tissue, it is doubtful whether they will have an active role in the management of prostate cancer.
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PMID:The distribution of PSA, cathepsin-D, and pS2 in BPH and cancer of the prostate. 127 46

The distribution of the estrogen inducible pS2 protein was investigated in benign and malignant prostate tissue by the avidin-biotin complex method. Prostate tissue obtained from 20 patients without clinical and histological evidence of malignant disease consistently lacked pS2 immunoreactivity. Conversely, nonneoplastic tissue from 36 total prostatectomies with locally advanced prostate cancer showed a variable degree of pS2 reactivity in normal or hyperplastic glands and in prostatic intraepithelial neoplasia (PIN) adjacent to the cancerous lesions. This suggests that the pS2 gene expression detected in nonmalignant tissue may be related to early premalignant changes of prostate glands harboring significant carcinomas. In prostate cancer the pS2 protein was detected in close association with neuroendocrine (NE) differentiation as assessed by Chromogranin A (Chr A) immunoreactivity. Double labeling techniques showed that pS2 immunoreactivity recognizes both endocrine (Chr A-positive) and adjacent exocrine (Chr A-negative) cell types within NE foci. Whereas pS2 expression was consistently confined to NE differentiation in untreated tumors, carcinomas that relapsed after hormonal therapy showed increased pS2 immunoreactivity, even in the absence of NE features. The differential expression of the pS2 peptide in nonneoplastic tissue from patients with and without malignant disease indicates that pS2 immunohistochemistry may be useful in the diagnostic evaluation of negative biopsy specimens. Furthermore, the results suggest that the immunohistochemical spectrum of pS2 in prostate cancer may include endocrine differentiated and presumably related cell populations.
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PMID:Differential expression of the pS2 protein in the human prostate and prostate cancer: association with premalignant changes and neuroendocrine differentiation. 763 45

Genistein, a component of soy products, may play a role in the prevention of breast and prostate cancer. However, little is known about the molecular mechanisms involved. In the present study, we examined the effects of genistein on the estrogen receptor positive human breast cancer cell line MCF-7. We observed that genistein stimulated estrogen-responsive pS2 mRNA expression at concentrations as low as 10(-8) M and these effects can be inhibited by tamoxifen. We also showed that genistein competed with [3H]estradiol binding to the estrogen receptor with 50% inhibition at 5 x 10(-7) M. Thus, the estrogenic effect of genistein would appear to be a result of an interaction with the estrogen receptor. The effect of genistein on growth of MCF-7 cells was also examined. Genistein produced a concentration-dependent effect on the growth of MCF-7 cells. At lower concentrations (10(-8)-10(-6) M) genistein stimulated growth, but at higher concentrations (> 10(-5) M) genistein inhibited growth. The effects of genistein on growth at lower concentrations appeared to be via the estrogen receptor pathway, while the effects at higher concentrations were independent of the estrogen receptor. We also found that genistein, though estrogenic, can interfere with the effects of estradiol. In addition, prolonged exposure to genistein resulted in a decrease in estrogen receptor mRNA level as well as a decreased response to stimulation by estradiol.
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PMID:Molecular effects of genistein on estrogen receptor mediated pathways. 862 49

pS2 protein expression has been demonstrated in a range of malignant tissues in an oestrogen-independent pathway. Recently, it has been demonstrated that pS2, in prostate cancer, is closely associated with neuro-endocrine differentiation. In the present study, we have analyzed, by immunohistochemistry along with microwave antigen retrieval, the expression of pS2 protein in a retrospective series of 236 human primary neuro-endocrine tumours and attempted to correlate this with the clinicopathologic features of patients and the presence of oestrogen receptor (ER). pS2 immunoreactivity was detected in 42% of small-cell lung carcinomas, 36% of lung carcinoids, 33% of phaeochromocytomas, 38% of carotid-body tumours, 31% of pancreatic neuro-endocrine tumours, 60% of stomach carcinoids, 55% of ileal carcinoids, 23% of appendiceal carcinoids and 86% of rectal carcinoids respectively in more than 10% tumour cells. No pituitary tumours displayed pS2 immunoreactivity. pS2 transcript was also detected in lung carcinoid and carotid-body tumours by Northern-blot analysis. There was a statistically higher incidence of pS2 expression in carcinoid tumours of the ileum and rectum than in those of the appendix. No association was observed between pS2 expression and the occurrence of the carcinoid syndrome; nor was any correlation observed between the occurrence of pS2 immunoreactivity and that of ER. Our results suggest that the expression of the pS2 protein in a wide spectrum of neuro-endocrine tumours may be implicated in the pathogenesis and progression of some neuro-endocrine tumours in an oestrogen-independent pathway.
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PMID:Expression of a breast-cancer-associated protein (pS2) in human neuro-endocrine tumours. 922 3

Medullary thyroid carcinoma (MTC) is an uncommon tumour of calcitonin-secreting C-cells of the thyroid gland. This cancer represents an important potential model for the study of mechanisms of human epithelial cell transformation. Although recent studies have identified the gene involved in familial forms of MTC, little is known about the molecular pathogenesis of the sporadic variants of this tumour. The biological and prognostic significance of TFF1 expression, particularly in diverse human malignancies, suggests that the TFF1 protein could have a role in human neoplasia. Furthermore, in prostate cancer it has been demonstrated that TFF1 expression is closely associated with premalignant changes and neuroendocrine differentiation. In the present study, the expression of TFF1 was analysed in 18 human MTCs, comprising sporadic and familial tumours, C-cell hyperplasia, and one case of lymph gland metastasis. TFF1 expression was also examined in the cultures of a human MTC-derived tumour cell line (TT cell line). The results showed that ten sporadic tumours, three hereditary tumours (including C-cell hyperplasia), and one lymph gland metastasis displayed TFF1 immunoreactivity. Indirect fluorescence immunocytochemistry and Western blotting revealed that the TFF1 protein was strongly expressed in the TT cells. Northern analysis revealed that tumours and TT cells expressed the TFF1 transcript. Although the function of TFF1 protein in the carcinogenesis of MTC remains to be elucidated, its expression in the majority of cases of both sporadic and hereditary tumours, metastatic tumours, and in C-cell hyperplasia suggests that it may contribute to the pathogenesis of MTC.
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PMID:TFF1 gene expression in human medullary thyroid carcinoma. 966 7

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

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

The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-alpha] in human breast and prostate cancer cell lines. In this study, we found that breast cancer-associated mutations of BRCA1 abolish or reduce its ability to inhibit ER-alpha activity and that domains within the amino- and carboxyl-termini of the BRCA1 protein are required for the inhibition. BRCA1 inhibition of ER-alpha activity was demonstrated under conditions in which a BRCA1 transgene was transiently or stably over-expressed in cell lines with endogenous wild-type BRCA1 and in a breast cancer cell line that lacks endogenous functional BRCA1 (HCC1937). In addition, BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D. The BRCA1 protein was found to associate with ER-alpha in vivo and to bind to ER-alpha in vitro, by an estrogen-independent interaction that mapped to the amino-terminal region of BRCA1 (ca. amino acid 1-300) and the conserved carboxyl-terminal activation function [AF-2] domain of ER-alpha. Furthermore, several truncated BRCA1 proteins containing the amino-terminal ER-alpha binding region blocked the ability of the full-length BRCA1 protein to inhibit ER-alpha activity. Our findings suggest that the amino-terminus of BRCA1 interacts with ER-alpha, while the carboxyl-terminus of BRCA1 may function as a transcriptional repression domain. Oncogene (2001) 20, 77 - 87.
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PMID:Role of direct interaction in BRCA1 inhibition of estrogen receptor activity. 1124 6

In the present study, we demonstrate that Rosiglitazone (Rosi), a thiazolidinedione and PPARgamma agonist, induces ERE (Estrogen Receptor Response Element) reporter activity, pS2 (an endogenous ER gene target) expression, and proliferation of ER positive breast cancer (MCF-7) cells. By performing a dose-response assay, we determined that high concentrations of Rosi inhibit proliferation, while low concentrations of Rosi induce proliferation. Using the anti-estrogen ICI, ER negative breast cancer (MDA-MB-231) cells, and a prostate cancer cell line (22Rv1) deficient in both ERalpha and PPARgamma, we determined that Rosiglitazone-induced ERE reporter activation and proliferation is through an ERalpha dependent mechanism. Rosiglitazone-induced ERE activation is also dependent on activation of the Extracellular Signal-Regulated Kinase-Mitogen Activated Protein Kinase (ERK-MAPK) pathway, since it is inhibited by co-treatment with U0126, a specific inhibitor of this pathway. We also demonstrate that when ERalpha and PPARgamma are both present, they compete for Rosi, inhibiting each others transactivation. To begin to unravel the pharmacological mechanism of Rosi-induced ER activation, sub-maximally effective concentrations of E(2) were used in combination with increasing concentrations of Rosi in luciferase reporter assays. From these assays it appears that E(2) and Rosi both activate ERalpha via similar pharmacological mechanisms. Furthermore sub-maximally effective concentrations of E(2) and Rosi additively increase both ERE reporter activity and MCF-7 cell proliferation. The results of this study may have clinical relevancy for Rosi's use both as an anti-diabetic in post-menopausal women and as an anti-cancer drug in women with ER positive breast cancer.
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PMID:Transactivation of ERalpha by Rosiglitazone induces proliferation in breast cancer cells. 1745 34

Trefoil factors, mucin-associated peptides, are overexpressed in prostate cancer (PC). We hypothesized that promoter methylation contributes to the regulation of trefoil factors (TFF1, TFF2 and TFF3) in human prostate cells. Here we show hypomethylation of promoter regions of TFF1 and TFF3 in PC cell lines with significant TFF expression as compared to benign immortalized prostate cell lines and PC cell lines not expressing trefoil factor. The most striking difference was observed for CpG sites located close to the AUG start codon overlapping several putative binding sites for cellular transcription factors. TFF2 was hypermethylated and had no or very low expression in all prostate cell lines investigated. Treatment of methylated cell lines with 5-aza-2'-deoxycytidine restored TFF expression in cell lines not expressing TFF and increased expression significantly in low-expressing cell lines. In clinical samples, methylation of the promoter/enhancer regions of TFF1 and TFF3 was significantly lower in PC compared to benign prostatic hyperplasia. The present study shows an inverse relation between promoter methylation and expression of trefoil factors. Preliminary analysis on clinical samples suggests that this regulatory mechanism is responsible for the increased levels of TFF1 and TFF3 observed in PC. The overexpression and promoter hypomethylation of trefoil factors may serve as biomarkers in PC.
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PMID:Promoter hypomethylation and upregulation of trefoil factors in prostate cancer. 2011 43


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