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)

Licorice root contains chemically diverse compounds that exhibit estrogenic effects in vitro and in vivo. The chalcone isoliquiritigenin (ISL) is a component of licorice extract exhibiting either antitumorigenic activity or estrogen receptor (ER) alpha-dependent growth promoting effects on breast cancer cells. In order to contribute to a better understanding of this apparent paradox, we synthesized and ascertained the estrogenic properties of ISL using, as model systems, the hormone-sensitive MCF7 breast cancer cells and the steroid-independent HeLa cells. Transfection experiments reveal that ISL is able to transactivate the endogenous ER alpha in MCF7 cells and this is supported by the capability to induce down-regulation of ER alpha protein levels and up-regulation of pS2 mRNA. Moreover, by using chimeric proteins consisting of the hormone binding domains of ER alpha and ER beta fused to the Gal4 DNA binding domain, we have determined that ISL is an estrogenic agonist of both ER isoforms. As a biological counterpart, low and intermediate ISL concentrations that induce substantial transcriptional activity stimulate the proliferation of MCF7 cells. However, high levels of ISL become cytotoxic even in steroid-receptor negative HeLa cells. Thus, the activity of ISL and the balance between risk or chemopreventive factor for estrogen-dependent breast cancer may depend on dietary intake.
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PMID:Estrogenic and antiproliferative activities of isoliquiritigenin in MCF7 breast cancer cells. 1258 38

Estrogen receptor beta (ERbeta) has been reported to have lower estradiol (E2)-induced transcriptional activity than human (h)ERalpha from estrogen response element (ERE)-driven reporters in transiently transfected cells. Conflicting data for activities of full-length and short hERbeta [hERbeta1, 530 amino acids (aa); and hERbeta1s, 477aa] have been reported. To test the hypothesis that hERbeta1 has higher transcriptional activity than hERbeta1s, we compared E2, 2,3-bis(4-hydroxyphenyl)propionitrile (a selective ERbeta agonist), and resveratrol-induced transcription by hERbeta1, hERbeta1s, and rat (r) ERbeta with hERalpha on different EREs in transiently transfected CHO-K1 and HEC-1A cells. Our results demonstrate for the first time that hERbeta1 has similar E2-induced activity to hERalpha and greater activity than rERbeta or hERbeta1s on a consensus palindromic ERE, either as a single or double copy; a minimal ERE; and the nonpalindromic pS2 ERE. 2,3-Bis(4-hydroxyphenyl)propionitrile showed greater efficacy with hERbeta1 and hERbeta1s than for rERbeta or hERalpha. We found that transcriptional differences between the ERbeta isoforms and ERalpha depend on the ERE sequence, confirming that the DNA sequence bound by ER is an allosteric effector of ER action. For the minimal 13-bp ERE and the pS2 ERE, the increase in transcriptional activity with hERbeta1 correlated with increased binding affinity. Coactivators steroid receptor coactivator-1 and cAMP response element binding protein-binding protein synergistically activated hERalpha and ERbeta transcription and showed reduced efficacy with rERbeta and hERbeta1s, suggesting a role for the N terminus of ERbeta1 in coactivator interaction. Collectively, these data indicate that the cellular expression of ERbeta isoforms may differentially impact ERE-regulated target gene expression in a ligand-dependent manner.
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PMID:Estrogen receptor beta isoforms exhibit differences in ligand-activated transcriptional activity in an estrogen response element sequence-dependent manner. 1450 May 65

Ginkgo biloba extracts (GBE) are extracted from the leaves of Ginkgo biloba tree. GBE contains 24% of phytoestrogens, which is kaempferol, quercetin, and isorhamnetin. It has been reported that phytoestrogens could be a part of SERMs (Selective estrogen receptor modulators) and possibly the alternative HRT (Hormone replacement therapy) for postmenopausal women. The goal of this study was to investigate the potencies of GBE and its major components (quercetin, kaempferol, isorhamnetin) for estrogenic effect, which confirms the capacity as an alternative HRP. It was found that GBE and its major components exerted a dual action on ER-alpha and ER-beta in competitive binding assay. The binding affinity of these chemicals to ER-beta was higher than to ER-alpha. In the E-screen assay, these chemicals induced cell proliferation in ER-positive MCF-7 cell, but not in ER-negative MDA-MB-231 cells. The cell proliferation induced by these chemicals was blocked by tamoxifen. Also, GBE and its major components induced pS2 and PR (progesterone receptor) transcription in MCF-7 cells. Therefore these results indicated that GBE and its major components had the weak estrogenic activities through the estrogen response pathway by an interaction with the ER. In conclusion, we provided the evidence of potential estrogenic activities of GBE, which could be useful as an alternative HRP. However, further studies are required to assess the physiological significance of GBE in animals and humans.
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PMID:Estrogenic activities of Ginkgo biloba extracts. 1470 64

Antiestrogen therapy of ductal carcinoma in situ (DCIS) has become a more common option in reducing risk of developing invasive cancer. Previously, estrogen receptor alpha (ER-alpha) was evaluated as the only predictive factor. Immunohistochemical staining was performed for ER-alpha, estrogen receptor ER-beta, progesterone receptor (PR), pS2 and her-2/neu in 59 cases of ductal carcinoma in situ (DCIS). We observed a positive correlation between the expression of ER-alpha (p=0.003), PR (p<0.001) and histopathological grading. Of the DCIS, 61.5% of ER-beta positive (p=0.046) and 35.5% of PR positive samples showed a coexpression with pS2, whereas 72.1% of pS2 negative DCIS were also negative for ER-beta and 92.9% of PR negative DCIS were negative for pS2 (p=0.012). In contrast, 50.0% of her-2/neu negative DCIS expressed ER-beta receptor (p=0.052). We propose that there are subpopulations of DCIS which can be described by distinct endocrine-associated expression patterns.
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PMID:Estrogen receptor alpha and beta, progesterone receptor, pS2 and HER-2/neu expression delineate different subgroups in ductal carcinoma in situ of the breast. 1537 87

We have recently identified the hADA3 protein, the human homologue of yeast transcriptional coactivator yADA3, as a novel HPV16 E6 target. Using ectopic expression approaches, we further demonstrated that hADA3 directly binds to the 9-cis retinoic acid receptors alpha and beta, and functions as a coactivator for retinoid receptor-mediated transcriptional activation. Here, we examined the role of endogenous hADA3 as a coactivator for estrogen receptor (ER), an important member of the nuclear hormone receptor superfamily. We show that ADA3 directly interacts with ER alpha and ER beta. Using the chromatin immunoprecipitation assay, we also show that hADA3 is a component of the activator complexes bound to the native ER response element within the promoter of the estrogen-responsive gene pS2. Furthermore, using an ER response element-luciferase reporter, we show that overexpression of ADA3 enhances the ER alpha- and ER beta-mediated sequence-specific transactivation. Reverse transcription-PCR analysis showed an ADA3-mediated increase in estrogen-induced expression of the endogenous pS2 gene. More importantly, using RNA interference against hADA3, we demonstrate that inhibition of endogenous hADA3 inhibited ER-mediated transactivation and the estrogen-induced increase in the expression of pS2, cathepsin D, and progesterone receptor, three widely known ER-responsive genes. The HPV E6 protein, by targeting hADA3 for degradation, inhibited the ER alpha-mediated transactivation and the protein expression of ER target genes. Thus, our results demonstrate that ADA3 directly binds to human estrogen receptor and enhances the transcription of ER-responsive genes, suggesting a broader role of mammalian hADA3 as a coactivator of nuclear hormone receptors and the potential role of these pathways in HPV oncogenesis.
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PMID:Human ADA3 binds to estrogen receptor (ER) and functions as a coactivator for ER-mediated transactivation. 1549 19

Androgen receptor (AR) is known to be expressed in approximately 70 to 90% of invasive breast cancers, but there are still conflicting data in terms of AR expression in ductal carcinoma in situ (DCIS). The aim of this study was to evaluate AR expression in DCIS and to compare these results with nuclear grading and with other common endocrine-related markers. On this basis the authors performed immunohistochemical staining for estrogen receptor (ER)-alpha and ER-beta, progesterone receptor (PR), pS2, her-2/neu, and AR in 59 cases of DCIS (24 low grade, 5 intermediate grade, 30 high grade). They found a strong correlation of expression of ER-alpha (P=0.003), PR (P<0.0001), and nuclear grading. For AR expression, 44.1% of all DCIS were positive, but there was no correlation between nuclear grading (P=0.535) and the expression of the other factors. The authors conclude that AR expression in DCIS is not correlated with nuclear grading and with the expression of other known endocrine-related markers such as ER-alpha and -beta, PR, pS2, and her-2/neu. The immunohistochemical assessment of AR status, therefore, may not help in providing a more objective way of classifying DCIS.
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PMID:Androgen receptor expression in ductal carcinoma in situ of the breast: not a helpful marker for classification such as estrogen receptor alpha and progesterone receptor. 1572 90

Differential signalling between the two oestrogen receptor (ER) isoforms in the presence of tamoxifen has been described. We hypothesise that differential recruitment of the steroid receptor co-activator, SRC-3 to ER-alpha and ER-beta may in part explain associations between ER isoforms and response to endocrine treatment. SRC-3 was localised within epithelial cells of breast tumour tissue and was co-localised with ER-alpha and ER-beta, (n=112). Expression of SRC-3 was found to be positively associated with ER-alpha (P=0.0021) and inversely with ER-beta (P<0.0001). Uniquely, this study utilises primary cell cultures derived from patient tumours, thus providing samples not readily available in most molecular model systems. These samples have enabled us to investigate the influence of growth factor pathways on steroid receptor-co-activator interactions. In HER2 (human epidermal growth factor receptor 2) positive primary tumour cell cultures 17beta-estradiol induced a decrease in SRC-3, whereas upregulated SRC-3 expression. Furthermore, treatment with tamoxifen-induced SRC-3 recruitment to the ER-oestrogen response element and enhanced interaction between SRC-3 and ER-alpha, but not ER-beta. Knockdown of SRC-3 results in a concomitant loss of expression of the oestrogen target gene pS2. Furthermore, silencing of SRC-3 resensitizes endocrine resistant, HER2 positive cells to the anti-proliferative effects of tamoxifen. The ability of ER-alpha, but not ER-beta to recruit SRC-3 in the presence of tamoxifen may in part explain the differential ER isoform associations with recurrence in human breast cancer.
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PMID:Tamoxifen-induced ER-alpha-SRC-3 interaction in HER2 positive human breast cancer; a possible mechanism for ER isoform specific recurrence. 1715 59

pS2 or TFF1 is a member of the trefoil factor family, which is distributed throughout the gastrointestinal tract in both normal and diseased tissues. It is also considered to be one of the major estrogen-regulated proteins and an indicator of estrogen receptor (ER) functionality. pS2 has previously been investigated in benign and malignant prostate lesions with little information about its relationship to steroid receptor status. Our purpose was to correlate pS2 expression with steroid receptor status (ER alpha and progesterone receptor (PR)) and other pathologic variables in prostate carcinoma. 15 benign prostate hyperplasia (BPH) and 47 prostate carcinoma cases were investigated by means of immunohistochemistry for pS2, ER and PR expression. 80% of BPH showed pS2 cytoplasmic immunoreactivity in hyperplastic acini and about half of these cases also exhibited nuclear staining decorating basal or both basal and luminal nuclei. pS2 was highly expressed in prostate carcinoma (91.4%) with both cytoplasmic and nuclear patterns of staining. The latter pattern was significantly associated with carcinoma having a low Gleason score (p=0.02). pS2 lacked any significant correlation with steroid receptor status, stage or grade. Univariate survival analysis revealed a significant impact of stage (p=0.03) and nodal status (p<0.0001) on patient outcome. The diagnostic value of pS2 expression in prostate carcinoma validated 74.19% accuracy, 91.48% sensitivity and 78.18% positive predictive value. The high sensitivity of pS2 expression in prostate carcinoma could make it a suitable marker for diagnosis of prostate carcinoma, especially in metastatic cases of unknown origin. The absence of correlation and dissimilarity in immunolocalization between pS2 and ER alpha leads to the assumption that ER alpha could not be the regulatory protein for pS2 and may raise questions about the functionality of ER alpha in prostate. The nuclear pattern of pS2 immunoreactivity either in benign or malignant prostatic lesions is similar to the published data on ER beta distribution and could also identify a subset of carcinoma patients with a favorable prognosis.
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PMID:pS2 (TFF1) expression in prostate carcinoma: correlation with steroid receptor status. 1913 93

Histone deacetylase inhibitors (HDIs) are valuable drugs in breast cancer where estrogen receptor alpha (ER alpha) can be silenced by epigenetic modifications. We report the effect of the clinically available HDI, valproic acid (VPA), on ER alpha expression and function in ER-negative breast cancer cells, MDA-MB-231. VPA induced ER alpha mRNA and protein, while did not modify ER beta. In VPA-treated cells, we also observed: (1) a correct transcriptional response to estradiol after transfection with the luciferase gene under the control of an estrogen-responsive minimal promoter (ERE-TKluc); (2) increased expression of the ER-related transcription factor FoxA1; (3) estradiol-induced up-regulation of several estrogen-regulated genes (e.g. pS2, progesterone receptor); (4) inhibitory effect of tamoxifen on cell growth. In conclusion, the HDI VPA, inducing ER alpha and FoxA1, confers to MDA-MB 231 cells an estrogen-sensitive "phenotype", restoring their sensitivity to antiestrogen therapy.
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PMID:Valproic acid restores ER alpha and antiestrogen sensitivity to ER alpha-negative breast cancer cells. 1977 91

This study aimed to elucidate which component of flaxseed, i.e. secoisolariciresinol diglucoside (SDG) lignan or flaxseed oil (FO), makes tamoxifen (TAM) more effective in reducing growth of established estrogen receptor positive breast tumors (MCF-7) at low circulating estrogen levels, and potential mechanisms of action. In a 2 x 2 factorial design, ovariectomized athymic mice with established tumors were treated for 8 wk with TAM together with basal diet (control), or basal diet supplemented with SDG (1 g/kg diet), FO (38.5 g/kg diet), or combined SDG and FO. SDG and FO were at levels in 10% flaxseed diet. Palpable tumors were monitored and after animal sacrifice, analyzed for cell proliferation, apoptosis, ER-mediated (ER-alpha, ER-beta, trefoil factor 1, cyclin D1, progesterone receptor, AIBI), growth factor-mediated (epidermal growth factor receptor, human epidermal growth factor receptor-2, insulin-like growth factor receptor-1, phosphorylated mitogen activated protein kinase, PAKT, BCL2) signaling pathways and angiogenesis (vascular endothelial growth factor). All treatments reduced the growth of TAM-treated tumors by reducing cell proliferation, expression of genes, and proteins involved in the ER- and growth factor-mediated signaling pathways with FO having the greatest effect in increasing apoptosis compared with TAM treatment alone. SDG and FO reduced the growth of TAM-treated tumors but FO was more effective. The mechanisms involve both the ER- and growth factor-signaling pathways.
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PMID:Dietary flaxseed lignan or oil combined with tamoxifen treatment affects MCF-7 tumor growth through estrogen receptor- and growth factor-signaling pathways. 1990 59


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