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)

Breast cancer is the most common malignant tumor among women, comprising an estimated 24% of all cancer cases and 18% of all cancer deaths. At least half of the patients with primary breast cancer will ultimately die by metastatic disease. The tumor characteristics, the natural course of the disease and the response to therapy vary strongly. A number of recently detected cell biological parameters such as oncogenes/suppressor genes, growth factors and secretory proteins are more or less important prognostic factors, because they influence the characteristics and behavior of a tumor with respect to metastatic pattern, extent of cellular differentiation, growth rate and response to treatment. However, there is no clear consensus how best to identify patients at high or low risk. In our experience c-myc amplification and pS2 protein are strong prognosticators for relapse rate, while in advanced disease (apart from a negative estrogen/progesterone receptor/pS2 status) amplification of HER2/neu is a good prognosticator for failure to endocrine therapy. In the diagnosis of breast cancer, in vivo imaging of tumors by labeled hormones or other factors also forms a new development which might have implications for treatment too. With respect to treatment both endocrine and chemotherapy can cure a minority of patients with micrometastases, but in patients with advanced disease only a prolongation of (progression-free) survival can be reached. Response rates decrease with increasing tumor load. In the past decade a number of interesting new endocrine agents has been developed such as new (pure) (anti)steroidal agents, vitamins, aromatase inhibitors, analogs of peptide hormones, prolactin inhibitors and growth factor antagonists. However, less is known on the (potential) interaction between hormones, chemotherapeutic agents, retinoids, cytokins, growth factor antagonists and irradiation. Rapid detection of new powerful combination therapies are needed to improve treatment results during the nineties.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Clinical breast cancer, new developments in selection and endocrine treatment of patients. 144 97

Studies on estrogen receptor (ER)-positive human breast cancer cell lines have shown that estrogen treatment positively modulates the expression of the genes encoding transforming growth factor-alpha (TGF alpha), 52-kDa cathepsin-D, and pS2. To determine whether these genes would be similarly regulated by estrogens in normal human mammary epithelial cells, we stably transfected immortal nontumorigenic human mammary epithelial cells with an ER-encoding expression vector. ER-negative tumor cells were also transfected for comparison. Levels of TGF alpha and 52-kDa cathepsin-D mRNA were enhanced by estrogen treatment of both ER-transfected immortal and tumorigenic cells, demonstrating that the ER by itself is sufficient to elicit estrogenic regulation of the expression of these genes. In contrast, expression of the pS2 gene was detected only in the ER-transfected tumor cells. The ER in both cell lines is capable of recognizing the pS2 promoter, however, since estrogen enhanced the activity of an introduced pS2-CAT reporter plasmid in transient expression analyses. These and other experiments with somatic cell hybrids between the immortal cells and ER+/pS2+ MCF-7 tumor cells, where pS2 gene expression is extinguished, support the conclusion that the immortal nontumorigenic cells encode gene products that block endogenous pS2 expression. These results also imply that such repressors are not active in the tumor cells.
Mol Endocrinol 1991 Nov
PMID:Induction of estrogen-regulated genes differs in immortal and tumorigenic human mammary epithelial cells expressing a recombinant estrogen receptor. 166 44

We have introduced the human estrogen receptor (ER) gene into HeLa cells, a human adenocarcinoma cell line of uterine origin, by infection. The ER cDNA was inserted into a retroviral vector (pMV7-ER) which also contains the neomycin resistance gene to allow for selection of stable infected clones. Northern analysis showed exogenous ER expression in stable clones. The ER protein expressed was about 66 kDa, similar to native MCF-7 ER, and binds with high affinity to estrogen (E2). We have also observed that addition of E2 at 10(-8) M inhibits the growth of the I-1 clone which expresses high levels of the ER (223 fmol/mg cytosol protein). The inhibitory effects of E2 directly correlate with the quantity of ER in the cells. E2-induced gene expression analysis showed that pS2 and progesterone receptor (PgR), genes induced in MCF-7 cells by E2, are not induced in the ER+ HeLa clones. However, c-myc expression was found to be decreased and may be responsible for the observed growth inhibition by E2.
Mol Cell Endocrinol 1991 Jun
PMID:Stable expression of the human estrogen receptor in HeLa cells by infection: effect of estrogen on cell proliferation and c-myc expression. 168 89

We have examined the ability of estradiol (E2) to regulate the expression of three mRNAs [for pS2, progesterone receptor (PR), and estrogen receptor (ER)], known to be under E2 regulation in the parental E2 growth-responsive MCF-7 cells, in an E2 growth-independent MCF-7 K3), previously isolated from the parental estrogen-dependent MCF-7 K1 human breast cancer cells after long term growth in vitro in the absence of estrogen, acquired estrogen-independent growth in vitro as well as the ability to form tumors in nude mice in vivo without estrogen. We find that the content of pS2 mRNA and the transcription rate of the pS2 gene, while being markedly increased by E2 in MCF-7 K1 cells, are no longer stimulated by E2 in this subline, although protein kinase activators tremendously increase (greater than 10-fold) pS2 mRNA in both K1 and K3 cells. In fact, basal pS2 mRNA levels are elevated 2.8 +/- 0.4-fold in MCF-7 K3 cells, and E2 evokes a concentration-dependent suppression of the pS2 mRNA level. In contrast, PR mRNA in the K3 subline, as in the parental K1 cells, is still up-regulated by E2, and ER mRAN content and the ER mRNA transcription rate are still down-regulated by E2 and show normal E2 dose-response relationships, implying that the ER in this subline is functional. These results demonstrate that the progression to estrogen-independent growth in K3 cells is accompanied by a change in the regulation of some estrogen-induced genes by estrogen. While PR and ER retain normal patterns of regulation by E2, the pS2 gene in the estrogen growth-independent K3 subline is differentially affected and is no longer stimulated by E2. Our data suggest that this altered regulation of the pS2 gene is probably not caused by a defect of the ER or ER regulation in this subline.
Mol Endocrinol 1991 Sep
PMID:Differential regulation of gene expression by estrogen in estrogen growth-independent and -dependent MCF-7 human breast cancer cell sublines. 172 71

The binding affinity and relative estrogenic potency of 2-bromo-, 4-bromo-, 2-methyl- and 4-methylestradiol was evaluated in MCF-7 breast cancer cells. The relative binding affinities compared to estradiol were 47% for 2-methyl-, 25% for 4-methyl-, 37% for 4-bromo- and 17% for 2-bromoestradiol. However, both 2- and 4-methyl- as well as 2- and 4-bromoestradiol were able (a) to translocate the cytosolic estrogen receptor into the nucleus and (b) to induce the progesterone receptor in a concentration dependent manner. Finally, all ring-A substituted estrogens used in this study induced the pS2 mRNA as demonstrated by Northern-blotting. From these findings we conclude that 2-bromo-, 4-bromo-, 2-methyl- and 4-methylestradiol are agonistic ligands for the estrogen receptor in MCF-7 breast cancer cells.
J Steroid Biochem Mol Biol 1991 Sep
PMID:Methyl and bromo derivatives of estradiol are agonistic ligands for the estrogen receptor of MCF-7 breast cancer cells. 191 26

The prognostic value of EGF-R, IGF-1-R and SS-R, and of cytosolic estrogen-regulated pS2 protein, was studied in patients (pts) with primary breast and advanced ovarian cancer. Ovarian cancer tissues were negative for pS2 (by immunoradiometric assay) IGF-1-R and EGF-R contents (by ligand binding assay, LBA) were of no or moderate prognostic value for breast cancer pts (n = 214). For advanced ovarian cancer pts, EGF-R content determined by LBA (n = 55) showed no prognostic value, whereas EGF-R status (n = 35) determined by immunohistochemistry (MoAb 2E9) significantly correlated with progression of disease (P less than 0.05). In breast cancer pts, both SS-R and pS2 showed no association with tumor size, nodal status and grade. For pS2 the best cut-off level with respect to relapse-free (RFS) and overall survival (OS) was found to be 11 ng/mg protein. Both SS-R (1 g% SS-R+, n = 135; P less than 0.04) and pS2 (27% pS2+, n = 197; P less than 0.001), which were mainly positive in ER+ tumors, were of prognostic value, especially within the subgroups with ER+/PgR+ tumors. Also within N+ and No pts the 5-yr RFS and OS showed a difference between pS2+ and pS2- (33 and 54% for N+, and 31 and 13% difference for No pts). In summary, SS-R and pS2 are valuable prognosticators in breast cancer pts, and prognostic significance of EGF-R in ovarian cancer pts needs further study.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:Prognostic value of pS2 protein and receptors for epidermal growth factor (EGF-R), insulin-like growth factor-1 (IGF-1-R) and somatostatin (SS-R) in patients with breast and ovarian cancer. 217 64

We have examined the effects of reversibly and irreversibly binding estrogenic and antiestrogenic ligands for the estrogen receptor on pS2 RNA accumulation in MCF-7 human breast cancer cells and on pS2-chloramphenicol acetyl transferase (CAT) fusion gene expression in transfected MCF-7 cells. In MCF-7 cells grown in the absence of estrogens, the reversibly binding estrogen, estradiol, and the affinity labeling estrogen, ketononestrol aziridine, KNA, evoked a 13-fold increase in pS2 RNA level. The reversibly binding antiestrogen trans-hydroxytamoxifen and the affinity labeling antiestrogens tamoxifen aziridine or desmethylnafoxidine aziridine behaved as partial agonists/antagonists. In thymidine kinase-chloramphenicol acetyltransferase (tk-CAT) fusion genes containing a 1000 base pair fragment of the pS2 5'-flanking region encompassing the estrogen responsive element of the gene [pS2 (-1100/-90) tk-CAT], estradiol and ketononestrol aziridine evoked a marked stimulation of CAT activity and, in transfected cells grown in both the presence or absence of the weak estrogen phenol red, the antiestrogens behaved as partial agonists/antagonists. This pS2 5'-flanking region displayed both estrogen-dependent and estrogen-independent enhancer activity as monitored by stimulation of CAT activity. Hormonal regulation of the transfected pS2 fusion gene was similar to that observed in the native pS2 gene of MCF-7 cells; however, antiestrogens, while still partial agonists-antagonists, were relatively more agonistic on the transfected fusion gene than on the native gene. One antiestrogen (ICI 164,384) that behaved as a pure estrogen antagonist on the native gene was a partial agonist-antagonist of pS2 gene expression in the plasmid. This study illustrates that the hormonal regulation of the pS2 gene, as characterized by the agonist-antagonist balance of estrogens and antiestrogens, is influenced by the DNA context of the pS2 estrogen responsive element. Also, the fact that estrogens and antiestrogens that form covalent bonds with the estrogen receptor modulate activity of the native pS2 gene and the pS2-tk-CAT fusion gene in a manner similar to that of their reversibly binding counterparts suggests that it may be possible to use these irreversibly binding ligands to follow the interaction of hormone-receptor complexes with regions regulating estrogenic stimulation of the pS2 gene.
Mol Endocrinol 1988 Oct
PMID:Regulation of pS2 gene expression by affinity labeling and reversibly binding estrogens and antiestrogens: comparison of effects on the native gene and on pS2-chloramphenicol acetyltransferase fusion genes transfected into MCF-7 human breast cancer cells. 246 Jul 49

In MCF7 human breast cancer cells, cathepsin-D and pS2 mRNAs are specifically and directly induced by estrogens at the transcriptional level. We studied the regulation of expression of these two genes by growth factors that are also mitogenic in this cell line. We show that pS2 mRNA, like cathepsin-D mRNA, is rapidly induced 2- to 4-fold by epidermal growth factor. The effect of epidermal growth factor on these two mRNAs was dependent upon de novo protein synthesis, indicating a different mechanism of regulation than with estradiol. Other peptide growth factors, such as insulin, insulin-like growth factor I, and basic fibroblast growth factor, also increased up to 3-fold the steady state levels of the two mRNAs in MCF7 cells. The pS2 mRNA, but not cathepsin-D mRNA, was also induced up to 8-fold by protein kinase-C activation with 12-O-tetradecanoylphorbol-13-acetate, suggesting the possible involvement of this transduction pathway in pS2 mRNA induction. The effect of 12-O-tetradecanoylphorbol-13-acetate was time and dose dependent and required protein synthesis. In addition, treatment by agents elevating cAMP increased pS2 mRNA accumulation 4-fold, whereas it had no effect on cathepsin-D mRNA levels. These results demonstrate that cathepsin-D and pS2 genes are under complex regulation in MCF7 cells, since growth factors stimulate their expression via indirect mechanisms contrasting with the primary transcriptional effects of estrogens.
Mol Endocrinol 1989 Mar
PMID:Regulation of cathepsin-D and pS2 gene expression by growth factors in MCF7 human breast cancer cells. 266 75

A cDNA library has been constructed from the poly(A)+ mRNA of oestrogen-stimulated ZR-75-1 human breast cancer cells. Screening by differential hybridization has identified eight clones which are stimulated between 4- and 16-fold by oestrogen. Two clones (pLIV-1) that are stimulated 4-fold, hybridize to three different mRNA species. A further five recombinants encode for a mRNA 600 bp long which is induced greater than 16-fold and have been shown to cross-hybridize to the oestrogen-responsive clone, pS2, isolated from the MCF-7 breast cancer cell line. Oestradiol was shown to be without detectable effect upon the expression of mRNA for dihydrofolate reductase, which is reported to be oestrogen regulated in MCF-7 cells. Actin gene expression is also unresponsive to oestradiol in ZR-75-1 cells. These results suggest that pLIV-1 represents a previously unidentified mRNA that may be involved in the oestrogen-regulated growth of ZR-75-1 human breast cancer cells.
Mol Cell Endocrinol 1988 Oct
PMID:Effects of oestrogen on the expression of a 4.4 kb mRNA in the ZR-75-1 human breast cancer cell line. 290 3

Peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs) are nuclear hormone receptors that are activated by fatty acids and 9-cis-retinoic acid, respectively. PPARs and RXRs form heterodimers that activate transcription by binding to PPAR response elements (PPREs) in the promoter of target genes. The PPREs described thus far consist of a direct tandem repeat of the AGGTCA core element with one intervening nucleotide. We show here that the vitellogenin A2 estrogen response element (ERE) can also function as a PPRE and is bound by a PPAR/RXR heterodimer. Although this heterodimer can bind to several other ERE-related palindromic response elements containing AGGTCA half-sites, only the ERE is able to confer transactivation of test reporter plasmids, when the ERE is placed either close to or at a distance from the transcription initiation site. Examination of natural ERE-containing promoters, including the pS2, very-low-density apolipoprotein II and vitellogenin A2 genes, revealed considerable differences in the binding of PPAR/RXR heterodimers to these EREs. In their natural promoter context, these EREs did not allow transcriptional activation by PPARs/RXRs. Analysis of this lack of stimulation of the vitellogenin A2 promoter demonstrated that PPARs/RXRs bind to the ERE but cannot transactivate due to a nonpermissive promoter structure. As a consequence, PPARs/RXRs inhibit transactivation by the estrogen receptor through competition for ERE binding. This is the first example of signaling cross-talk between PPAR/RXR and estrogen receptor.
Mol Endocrinol 1995 Jul
PMID:Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements. 747 63


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