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)

Estrogen receptors (ERs) mediate most of the biological effects of estrogen in mammary and uterine epithelial cells by binding to estrogen response elements in the promoter region of target genes or through protein-protein interactions. Anti-estrogens such as tamoxifen inhibit the growth of ER-positive breast cancers by reducing the expression of estrogen-regulated genes. However, anti-estrogen-resistant growth of ER-positive tumors remains a significant clinical problem. Here we show that phosphatidylinositol (PI) 3-kinase and AKT activate ERalpha in the absence of estrogen. Although PI 3-kinase increased the activity of both estrogen-independent activation function 1 (AF-1) and estrogen-dependent activation function 2 (AF-2) of ERalpha, AKT increased the activity of only AF-1. PTEN and a catalytically inactive AKT decreased PI 3-kinase-induced AF-1 activity, suggesting that PI 3-kinase utilizes AKT-dependent and AKT-independent pathways in activating ERalpha. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT. In addition, LY294002, a specific inhibitor of the PI 3-kinase/AKT pathway, reduced phosphorylation of ERalpha in vivo. Moreover, AKT overexpression led to up-regulation of estrogen-regulated pS2 gene, Bcl-2, and macrophage inhibitory cytokine 1. We demonstrate that AKT protects breast cancer cells from tamoxifen-induced apoptosis. Taken together, these results define a molecular link between activation of the PI 3-kinase/AKT survival pathways, hormone-independent activation of ERalpha, and inhibition of tamoxifen-induced apoptotic regression.
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PMID:Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. 1113 88

To gain more detailed insight into the histogenesis of primary nonurachal adenocarcinomas and signet ring cell carcinomas of the urinary bladder, we analyzed by immunohistochemistry the expression of a broad panel of proteins, associated with cell differentiation (pS2 peptide, MUC5AC, MUC6, spasmolytic polypeptide, cyclooxygenases-1 and -2, caveolin-1), and of various novel known or candidate tumor suppressors (14-3-3 sigma, SYK, PTEN, maspin). Included were 12 adenocarcinomas admixed to urothelial carcinomas, 10 pure adenocarcinomas and 5 signet ring cell carcinomas. As the most important finding, the majority of signet ring cell carcinomas and three quarters of the adenocarcinomas (72.7%) expressed the pS2 peptide, and nearly half of the adenocarcinomas (45.5%) as well as most of the signet ring cell carcinomas were observed to secrete the MUC5AC apomucin. Since expression of both proteins was absent in the normal nonneoplastic urothelium, their tumor-associated appearance is regarded as a neoexpression or reexpression, respectively, of normally cryptic antigenic determinants, and is assumed to be involved in the phenotypical formation of vesical adenocarcinomas, including signet ring cell carcinomas. The expression of both pS2 and MUC5AC in variants of urothelial carcinomas with a glandular differentiation and an extracellular mucus production support the concept that adenocarcinomas may histogenetically develop from preexistent TCC. Adenocarcinomas which secrete the pS2 peptide and the MUC5AC glycoprotein are proposed to be subclassified as adenocarcinomas of the intestinal type, as distinguished from those of the common type lacking an expression. The tumor suppressor genes showed a loss of protein expression in adenocarcinomas, ranging from 54.5% (14-3-3 sigma), to 31.8 (PTEN), 27.3% (SYK) and 18.2% (maspin). Similar expression profiles in the coexistent urothelial carcinomas argue against a specific involvement of these genes during the morphogenesis of adenocarcinomas.
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PMID:Tumor-associated neoexpression of the pS2 peptide and MUC5AC mucin in primary adenocarcinomas and signet ring cell carcinomas of the urinary bladder. 1828 38

Resistance to endocrine therapy is a major clinical problem in breast cancer. The role of ERalpha splice variants in endocrine resistance is largely unknown. We observed reduced protein expression of an N-terminally truncated ERalpha46 in endocrine-resistant LCC2, LCC9, and LY2 compared to MCF-7 breast cancer cells. Transfection of LCC9 and LY2 cells with hERalpha46 partially restored growth inhibition by TAM. Overexpression of hERalpha46 in MCF-7 cells reduced estradiol (E(2))-stimulated endogenous pS2, cyclin D1, nuclear respiratory factor-1 (NRF-1), and progesterone receptor transcription. Expression of oncomiR miR-21 was lower in TAM-resistant LCC9 and LY2 cells compared to MCF-7 cells. Transfection with ERalpha46 altered the pharmacology of E(2) regulation of miR-21 expression from inhibition to stimulation, consistent with the hypothesis that hERalpha46 inhibits ERalpha activity. Established miR-21 targets PTEN and PDCD4 were reduced in ERalpha46-transfected, E(2)-treated MCF-7 cells. In conclusion, ERalpha46 appears to enhance endocrine responses by inhibiting selected ERalpha66 responses.
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PMID:Estrogen receptor alpha 46 is reduced in tamoxifen resistant breast cancer cells and re-expression inhibits cell proliferation and estrogen receptor alpha 66-regulated target gene transcription. 2030 9

Senescence is a cellular stress response characterized by persistent cell growth arrest under various stress conditions, including oncogene activation or tumor suppressor loss, which functions as a critical barrier that must be overcome to allow the progression from a precancerous or preinvasive lesion to a malignant tumor. Trefoil factor 1 (TFF1) is a secreted protein involved in maintaining the gastrointestinal epithelium by serving a tumor-suppressive role; however, TFF1 is overexpressed in several types of cancers. Here we report that TFF1 acts as a promoter of tumorigenesis in the context of prostate and pancreatic cancers by suppressing oncogene-induced senescence (OIS). Expression of TFF1 allows human prostate epithelial cells to escape OIS caused by the activated Ras oncogene or by reduced expression of the tumor suppressor PTEN, in part by the involvement of the EGF receptor-mediated pathway and inhibition of the expression of the cell cycle regulator p21. Without intrinsic promitogenic activity TFF1 may act in both autocrine and paracrine manners to enable cells to undergo the initial transformation and expansion against the restrictive microenvironment during early stage tumorigenesis. Taken together, our findings identify TFF1 as a soluble factor designed to act mainly to antagonize the OIS process to accelerate tumorigenesis.
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PMID:Trefoil factor 1 acts to suppress senescence induced by oncogene activation during the cellular transformation process. 2145 Nov 35

AIB1 was involved in the development and progression of breast cancer. Although it was found that AIB1 could be phosphorylated by some kinases including PI3K, the function of AIB1 and AKT interaction in breast cancer is not well defined. MCF-7 cells were transfected with pERE-Luc AKT and/or AIB1 plasmids, and then ERE luciferase activity in presence or absence of estrogen (E2) were measured. Plasmids containing PTEN and an PI3K inhibitor LY294002 were transfected into or treated cells to identify the interaction of PI3K/AKT and activation of AIB1, and examine their roles in cell cycle regulation. The AKT phosphorylation activity was evaluated by kinase assay using H2B as a substrate. The association between A1B1 and pS2 promoter was detected by the Chromatin Immunoprecipitation (ChIP) assay. AIB1 and AKT in the same complex were detected by Pull-down assay. IGF-1 can increase AIB1 recruitment to PS2 and enhance the ER-dependent transcription activity through the PI3K/AKT pathway. AIB1 associate with AKT to regulate cell cycle. The special relations concerning the AIB1 and AKT may arouse some new viewpoints for potential therapeutic targets in breast cancer.
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PMID:The PI3K and AIB1 interaction is involved in estrogen treated breast cancer cells. 2980 3

Naturally-occurring somatic mutations in the estrogen receptor gene (ESR1) have been previously implicated in the clinical development of resistance to hormonal therapies, such as Tamoxifen. For example, the somatic mutation Y537S has been specifically associated with acquired endocrine resistance. Briefly, we recombinantly-transduced MCF7 cells with a lentiviral vector encoding ESR1 (Y537S). As a first step, we confirmed that MCF7-Y537S cells are indeed functionally resistant to Tamoxifen, as compared with vector alone controls. Importantly, further phenotypic characterization of Y537S cells revealed that they show increased resistance to Tamoxifen-induced apoptosis, allowing them to form mammospheres with higher efficiency, in the presence of Tamoxifen. Similarly, Y537S cells had elevated basal levels of ALDH activity, a marker of "stemness", which was also Tamoxifen-resistant. Metabolic flux analysis of Y537S cells revealed a hyper-metabolic phenotype, with significantly increased mitochondrial respiration and high ATP production, as well as enhanced aerobic glycolysis. Finally, to understand which molecular signaling pathways that may be hyper-activated in Y537S cells, we performed unbiased label-free proteomics analysis. Our results indicate that TIGAR over-expression and the Rho-GDI/PTEN signaling pathway appear to be selectively activated by the Y537S mutation. Remarkably, this profile is nearly identical in MCF7-TAMR cells; these cells were independently-generated in vitro, suggesting a highly conserved mechanism underlying Tamoxifen-resistance. Importantly, we show that the Y537S mutation is specifically associated with the over-expression of a number of protein markers of poor clinical outcome (COL6A3, ERBB2, STAT3, AFP, TFF1, CDK4 and CD44). In summary, we have uncovered a novel metabolic mechanism leading to endocrine resistance, which may have important clinical implications for improving patient outcomes.
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PMID:The ER-alpha mutation Y537S confers Tamoxifen-resistance via enhanced mitochondrial metabolism, glycolysis and Rho-GDI/PTEN signaling: Implicating TIGAR in somatic resistance to endocrine therapy. 3057 3