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)

The effects of tamoxifen, three of its in vivo metabolites and 3-hydroxytamoxifen on cellular proliferation and the induction of four oestrogen-regulated RNAs (pNR-1, pNR-2, pNR-25 and cathepsin D) have been measured in MCF-7 breast cancer cells in phenol red-free culture medium. Tamoxifen and 3-hydroxytamoxifen acted as partial oestrogens to stimulate cell growth and the levels of the pNR-2 and pNR-25 RNAs. They were full oestrogens for the induction of cathepsin D RNA and induced the pNR-1 RNA above the level found in oestrogen-treated cells. N-Desmethyltamoxifen and 4-hydroxytamoxifen behaved like tamoxifen except that N-desmethyltamoxifen did not induce the pNR-2 RNA and was only a partial oestrogen for the induction of cathepsin D RNA, and 4-hydroxytamoxifen did not induce the pNR-2 or pNR-25 RNAs. In the presence of oestradiol, the four anti-oestrogens prevented the stimulation of growth and reduced (pNR-2 and pNR-25) or increased (pNR-1) the RNA levels to those present in MCF-7 cells treated with the anti-oestrogen alone. In contrast, for cathepsin D RNA levels there was a synergistic effect of the anti-oestrogens and oestradiol. The concentration at which each anti-oestrogen was effective was related to its affinity for the oestrogen receptor. Metabolite E was a full oestrogen for the induction of cell proliferation and the oestrogen-regulated RNAs. pNR-25 and pNR-2 RNA levels correlated most closely with effects on cell proliferation. These RNAs are therefore potentially the most useful for predicting the response of breast cancer patients to tamoxifen therapy.
Br J Cancer 1989 May
PMID:Oestrogenic activity of tamoxifen and its metabolites on gene regulation and cell proliferation in MCF-7 breast cancer cells. 273 7

A complementary DNA library from MCF-7 cells was screened using 32P-cDNA derived from a breast carcinoma and from normal breast tissue. From 10(5) plaques (20% of library) we obtained a clone (Md2) which was differentially expressed in the carcinoma. The distribution of its corresponding transcript of 6-700 nucleotides was examined in normal and neoplastic cells, by filter and in situ hybridisation. We observed localisation of 35S-Md2 to the tumour cells of breast cancers with no significant reaction over stromal or vascular elements or on normal ductal epithelia. M13 sequencing showed Md2 to be 250 nucleotides in length, of which 197 were homologous to the 3'-untranslated region and a short open reading frame of the pS2 gene (Masiakowski et al., 1982). Md2 mRNA was found principally in breast carcinoma cell lines and tumours, with low levels in benign breast disease and no expression in non-breast squamous cell lines. Approximately 43% (23/54) of carcinomas contained this mRNA (varying from + to + + + + level); it was present in 20/38 (53%) of ER positive carcinomas compared to 3/16 (19%) of ER negative carcinomas. In 21 patients who had undergone primary endocrine therapy for recurrent disease expression of Md2 in the primary tumour correlated with the subsequent response to treatment (P = 0.041) and was of similar predictive value as ER status. Both tests correctly predicted outcome in about 76% of cases.
Br J Cancer 1989 Aug
PMID:Characterisation of a messenger RNA selectively expressed in human breast cancer. 276 62

The role of estrogen in the growth of human breast cancers has been investigated at two levels. First, we have studied the pS2 gene, whose transcription is stimulated by estrogen in the human breast cancer cell line, MCF-7. The pS2 gene product is a small, secreted polypeptide currently of unknown function, but with structural features similar to some growth factors. The expression of the pS2 gene has so far been detected only in MCF-7 cells and some breast cancer biopsies. Preliminary studies indicate that pS2 is a potential marker for hormone-dependent breast cancer. Ongoing studies will continue to focus on the implicated role of pS2 in the estrogen-mediated growth of breast cancers and its possible use as a marker for estrogen-dependent tumors. Second, we have analyzed the structure and function of the human ER. The receptor stimulates pS2 gene transcription by interacting with an ERE in the 5'-flanking region of that gene. A mutational analysis of the receptor protein has localized a DNA-binding domain, which determines target gene specificity, and a hormone-binding domain. These domains appear to be the only two regions of the receptor which are absolutely required for the transcription-activating function of the ER in transfection assays with reporter plasmids. The N-terminal region of the protein (regions A and B), which is necessary for increasing the efficiency of gene expression using the pS2 ERE, but not a vitellogenin ERE, may also play a role in transcription activation. Further progress in the characterization of the ER functional domains will require studies on target genes in a more physiological chromatin environment, as well as detailed physical analyses of receptor structure.
Cancer Treat Res 1988
PMID:Structure and function of the pS2 gene and estrogen receptor in human breast cancer cells. 290 50

The expression of genes which may be involved in the regulation of human mammary epithelial cell growth [transforming growth factors alpha and beta] and tumorigenesis [c-myc, erbB2, epidermal growth factor receptor (EGFR), Ha-ras, pS2] has been compared in similarly cultured normal cell strains and tumor cell lines. We have found that the normal breast cells produce high levels of EGFR mRNA, which are translated into nearly 10(5) low affinity epidermal growth factor-binding molecules/cell. In the estrogen receptor-negative lines examined, the EGFR gene was expressed at levels comparable to those in the normal cells. In contrast, EGFR and transforming growth factor alpha mRNAs were reduced in estrogen receptor-positive tumor lines compared to estrogen receptor-negative lines and normal cells. Steady state mRNA levels for transforming growth factor beta, erbB2, c-myc, and Ha-ras in the normal cells were greater than or comparable to those in all of the breast tumor lines. Furthermore, in the absence of gene amplification, only one of the genes examined (i.e., pS2) was overexpressed in a subset of the tumor cells compared to their normal counterparts. Several reports by other investigators have described overexpression of some of these genes in breast biopsies and in tumor lines in studies lacking normal controls. Thus, our results, in which the same genes were not overexpressed compared to normal cells unless amplified, underscore the importance of including appropriate normal controls in studies aimed at defining aberrant patterns of gene expression in tumor cells.
Cancer Res 1988 Dec 15
PMID:Expression of growth factors and oncogenes in normal and tumor-derived human mammary epithelial cells. 319 80

Two variants of the human estrogen-responsive breast cancer cell line MCF-7, were utilized to study the expression of an estrogen-induced gene, pS2, and an estrogen-induced Mr 52,000 protein. One variant cell line, I13, is growth inhibited after chronic exposure to estrogen. Both the pS2 gene product and the Mr 52,000 protein were produced at maximal levels at a time when I13 growth was inhibited by estrogen. The variant cell line, LY2, selected for its resistance to the growth-inhibitory effects of the antiestrogen, LY117018, grew normally in the presence of this drug, although both pS2 expression and Mr 52,000 protein production were inhibited. These results confirm that the pS2 gene and Mr 52,000 protein are estrogen-regulated elements, but the lack of correlation between their activities and variant cell growth suggests that they are not major autocrine growth-stimulatory agents.
Cancer Res 1986 Apr
PMID:Use of two MCF-7 cell variants to evaluate the growth regulatory potential of estrogen-induced products. 394 73

The growth of MCF-7 cells was arrested by 24 h of isoleucine deprivation. Following replenishment of the medium, the incorporation of uridine and thymidine into trichloroacetic acid-precipitable material began to increase slowly and gradually rose to the level of cycling cells. The addition of 5 X 10(-9) M estradiol to growth-arrested cells dramatically shortened the time of onset of macromolecular synthesis and increased the overall amount of precursor incorporation 2- to 4-fold over the level obtained by arrested control cells. The increase in uridine incorporation preceded the increase in thymidine incorporation by 6 h. Inhibition of protein synthesis with cycloheximide blocked the recovery of macromolecular synthesis in both control and estrogen-treated cells. Actinomycin D was ineffective in blocking the estrogen-stimulated recovery of macromolecular synthesis at concentrations known to inhibit pre-rRNA synthesis (10(-8) M). At higher concentrations, uridine and thymidine incorporation were inhibited in a dose-dependent manner. Inhibition of RNA polymerase II activity with alpha-amanitin similarly blocked both the recovery of the cells from isoleucine starvation and the potentiation of this by estradiol. Dihydrofolate reductase and thymidine kinase activities are both stimulated by estradiol in MCF-7 cells. In cycling cells, estrogen stimulates a 2-fold increase in their messenger RNAs (mRNAs) within 24 h. The level of dihydrofolate reductase mRNA is unaffected by isoleucine starvation, and estrogen caused no change in dihydrofolate reductase mRNA levels over a 24-h period following reversal of growth arrest. Similar results were observed for the 600-nucleotide pS2 mRNA that has been identified as an estrogen-induced RNA in MCF-7 cells. In contrast, thymidine kinase mRNA was found to be increased by estrogen at 24 h, but not at 12 h, following reversal of growth arrest. This increase correlates with increases in thymidine, but not uridine incorporation. These data indicate that the estrogen-stimulated increase in thymidine incorporation following release from growth arrest is dependent on new RNA synthesis. However, the hormone did not increase the levels of three estrogen-regulated mRNAs coordinately with the increases observed in uridine incorporation.
Cancer Res 1985 Jun
PMID:Relationship between the expression of estrogen-regulated genes and estrogen-stimulated proliferation of MCF-7 mammary tumor cells. 398 99

Recently, several carcinomas of the gastrointestinal tract were tested for pS2/BCEI activity, a gene isolated from breast-cancer cells and coding for a small secreted peptide. In the latter tumors, its activity is under estrogen control; surprisingly, it was also found expressed in carcinomas of the stomach, biliary tract and pancreas. We have now investigated the expression of this gene in 64 colorectal carcinomas, 31 adenomas and 13 polyps in comparison with their matrix tissues by applying molecular (RNA analysis) and immunohistochemical (pS2 antibody) techniques. Positive pS2 immunostaining (ranging from focal to strong immunoreaction) was noted in 89% of human colon cancers, while 11% remained negative. Furthermore, all 40 transitional mucosae were strongly positive, whereas normal mucosa was negative. Of hyperplastic polyps, 68.2% displayed a significant immunoreaction, and 80.6% of adenomas were focally positive. Finally, 6 out of 16 cases showed significant pS2 transcription in Northern blot analysis. These data clearly indicate that the breast-cancer-associated pS2 protein also plays an as yet undetermined role in the tumorigenesis of human colorectal carcinomas.
Int J Cancer 1994 Jan 02
PMID:Expression pattern of breast-cancer-associated protein pS2/BCEI in colorectal tumors. 750 65

BRCA1 mRNA and protein levels are regulated by the steroid hormones estrogen and progesterone in human breast cancer cells. BRCA1 mRNA and protein levels were significantly decreased in estrogen-depleted MCF-7 and BT20T cells and increased again after stimulation with beta-estradiol. The increase in BRCA1 expression upon stimulation with estrogen was not coordinated with the early induction of the estrogen-dependent pS2 gene but closely paralleled the delayed increase in the S-phase dependent marker cyclin A. T47-D cells deprived of steroid hormones and subsequently stimulated with progesterone also showed a delayed increase in BRCA1 mRNA expression. However, no change in BRCA1 protein was detected in these cells. When considered together, the data suggest that steroid hormones may affect BRCA1 expression indirectly by altering the proliferative status of the cells rather than acting directly on DNA sequences in the BRCA1 gene itself.
Cancer Res 1995 Oct 15
PMID:Hormone-dependent regulation of BRCA1 in human breast cancer cells. 755 29

For quantificative determination of ERBB2 gene amplification in archival human carcinoma specimens we have developed a rapid, non-radioactive approach, which is based on the differential polymerase chain reaction (PCR) and fluorescent DNA technique. Sequences from the ERBB2 gene and from a single-copy reference gene were amplified simultaneously by PCR, in which one of each primer pair was fluorescently labelled. PCR products were separated by polyacrylamide gel electrophoresis in an automated DNA sequencer and directly quantified after laser activation and emission scanning using appropriate software. This fluorescent differential polymerase chain reaction (fd-PCR) method was used for quantificative determination of ERBB2 gene amplification in 195 formalin-fixed, paraffin-embedded breast carcinoma tissues. ERBB2 gene amplification was found in 52 (26%) of these tumors and correlated significantly with tumor size, absence of estrogen receptor (ER) and pS2 expression, but not with absence of progesterone receptor (PR) or presence of epidermal growth factor receptor (EGF-R) expression, lymph-node metastases or grading. In univariate analysis, ERBB2 gene amplification showed no significant correlation with clinical outcome, either in the whole population or in the subgroup defined by positive axillary lymph-node metastases. However, within the node-negative subgroup, patients with ERBB2 gene amplification had significantly decreased relapse-free survival and overall survival (p < 0.05). The fd-PCR assay is a valuable tool for determination of amplification of ERBB2 gene as well as further oncogenes. In this way, more detailed information about individual tumor biology may be acquired by a routine assay.
Int J Cancer 1995 Oct 20
PMID:ERBB2 gene amplification detected by fluorescent differential polymerase chain reaction in paraffin-embedded breast carcinoma tissues. 759 Dec 99

Changes in estrogen receptor (ER) expression and function may explain the development of tamoxifen resistance in breast cancer. ER expression was measured by an immunohistochemical assay, validated for use in tamoxifen-treated tumors against a biochemical enzyme immunoassay, in 72 paired biopsies taken before treatment and at progression or relapse on tamoxifen. Progesterone receptor (PgR) and pS2 gene expression were also measured immunohistochemically as an indicator of ER function. Overall the frequency of ER expression was reduced from 37 of 72 (51%) pretamoxifen to 21 of 72 (29%) at progression or relapse, with a significant reduction in the quantitative level of ER (P < 0.0001; Wilcoxon signed rank sum test). Tumors treated with primary tamoxifen that responded but then developed acquired resistance frequently remained ER positive (ER+) at relapse: 16 of 18 (89%) were ER+ pretamoxifen (75% of these expressed either PgR or pS2) and 11 of 18 (61%) were ER+ at relapse (82% continued to express PgR or pS2). In contrast, only 3 of 20 (15%) tumors that progressed on primary tamoxifen with de novo resistance were ER+ pretamoxifen, and all tumors were ER- at progression. At progression, 6 of 20 (30%) of these tumors expressed high levels of PgR (mean H-score, 98) and/or pS2 (mean, 50% cells positive), despite being ER-. In tumors that recurred during adjuvant tamoxifen therapy, including locoregional and metastatic lesions, ER expression was significantly reduced from 18 of 34 (53%) in the original primary tumor to 10 of 34 (29%) at relapse (P = 0.002). PgR expression was likewise significantly reduced in this group (P = 0.001). This study confirms that expression of a functional ER in breast cancer is a strong predictor for primary response to tamoxifen. Although ER was reduced in tamoxifen-resistant tumors overall, the development of acquired resistance was associated with maintained ER expression and function in many tumors, whereas de novo resistance remained related to lack of ER expression. Recurrence during adjuvant tamoxifen was associated with development of an ER/PgR-negative phenotype in some tumors. These data imply that separate mechanisms of resistance may occur in these different clinical subgroups.
Cancer Res 1995 Aug 01
PMID:Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer. 761 68


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