Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-alpha (TNF-alpha) demonstrated antimitogenic activity in MCF-7 cells (estrogen receptor-positive human breast cancer cells) in a dose- and time-dependent manner (EC-50 of 2.5 ng/ml). This antimitogenic effect of TNF-alpha was accompanied by a decreased number of cells in S phase in a dose- and time-dependent manner. Based on growth arrest experiments using aphidicolin, it is apparent that TNF-alpha acted in early G1 phase. It did not show antimitogenic effects once cells reentered the S phase based on [3H]thymidine incorporation into DNA and cell cycle analysis. Specificity of TNF-alpha was established by using monoclonal anti-human TNF-alpha antibody. On the basis of Western immunoblot analysis of Rb, p53 and cell cycle inhibitory protein (Cip1) (p21) proteins, TNF-alpha decreased Rb protein expression in a dose- and time-dependent manner whereas it increased the expression level of tumor suppressor p53 protein. TNF-alpha also increased the expression level of Cip1 (p21) protein in a dose-dependent manner. This induction of Cip1 (p21) protein was preceded by the induction of p53 protein in MCF-7 cells. Cip1 (p21) protein associated with cyclin D was also increased. Tumor suppressor Rb protein expression was increased during G1 to S phase progression. Cyclin D protein expression levels were not changed in response to TNF-alpha treatment, although serine/threonine kinase inhibitors such as H7 and the protein kinase C inhibitor staurosporine decreased cyclin D expression levels in MCF-7 cells. Based on experiments with staurosporine, it appears that TNF-alpha does not utilize a protein kinase C pathway in MCF-7 cells. Other cell cycle-related proteins such as Cdk2, Cdc2, and Cdk4 did not show any change in response to TNF-alpha. TNF-alpha did not affect complexes between cyclin D and Cdk2, Cdk4, and Rb proteins in MCF-7 cells. Taken together these results suggest that Rb, p53, and Cip1 (p21) proteins mediate TNF-alpha antimitogenic activity, and TNF-alpha induces growth arrest in the G1 phase in MCF-7 cells.
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PMID:Effects of tumor necrosis factor-alpha on antimitogenicity and cell cycle-related proteins in MCF-7 cells. 762 60

The authors immunohistochemically studied the expression of the estrogen receptor (ER), 27-kD heat shock protein (HSP27) and pS2 in 118 invasive primary human breast cancers. Positive nuclear staining of the ER was detected in 64% of the cases and was closely correlated with the biochemical assay (p < 0.0001). ER-positive tumors were significantly decreased with tumor size and stage (p < 0.001 each), but not with lymph node status. Positivity of the ER was correlated with the cytoplasmic expression of HSP27 (p < 0.005), pS2 (not significant) and HSP70 (not significant). ER negativity was significantly correlated with the expression of p53, epidermal growth factor receptor (EGFR) and c-erbB-2 (p < 0.05 each). Thus, it was concluded that ER-positive breast carcinomas, relatively small in size, preferentially expressed HSP27, HSP70 and pS2 and that ER-negative tumors, relatively large in size, were predisposed to express p53, EGFR and c-erbB-2.
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PMID:Immunohistochemical detection of estrogen receptor in invasive human breast cancer: correlation with heat shock proteins, pS2 and oncogene products. 763 53

We introduce a new epithelial ovarian carcinoma cell line (UCI 107) from a patient with papillary adenocarcinoma of the ovary who had not been previously treated. The growth characteristics, chemosensitivity, tumorgenicity, cytogenetics, antigen expression, and receptor status were examined. A standardized photometric assay was implemented to determine the response to single drug agents including doxorubicin (ADR), cisplatin (CDDP), and Taxol. Tumorgenicity was determined utilizing female athymic mice implanted either subcutaneously (sc) or intraperitoneally (ip) with 1 x 10(7) UCI 107 cells. UCI 107 cells grow rapidly in culture with lag phase of approximately 48 hr, population doubling time of 24-36 hr, and saturation density of 4.8 x 10(5) cells/cm2. The 50% inhibitory concentration values for the chemotherapeutic agents were 0.170, 0.029, and 0.330 microM for ADR, Taxol, and CDDP, respectively. Nude mice produced ip tumors within 15 days, resulting in death from carcinomatosis 40-45 days postimplantation. Subcutaneous tumor nodules (100 mm3) were observed in nude mice 12-13 days post-tumor implantation reaching a maximum tumor volume of approximately 10,000 mm3 by Day 30. The cytogenetic composite karyotype is as follows: 46, X, der (X) t (X;7) (p11;q22), inv dup (1) (q12;q32), t (6;6;11;22) (p21.3;q16;q23.3;q13.3), del (13) (q14.1). The cell line expresses progesterone receptor, increased levels of p53 protein, and cytokeratins. It does not appear to express Her-2/neu protein, estrogen receptor, nor the CA 125 tumor marker. In conclusion, UCI 107 displays unique cellular properties which make it an attractive model for the study of ovarian cancer.
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PMID:Characterization and development of UCI 107, a primary human ovarian carcinoma cell line. 767 98

Breast carcinomas are known to express platelet-derived growth factor (PDGF), a known connective tissue mitogen. In order to further evaluate the potential role of PDGF in these epithelial tumors, expression of the PDGF B chain (PDGF-B) and the PDGF receptor beta subunit (PDGFR) was analyzed by immunocytochemistry and in situ hybridization in 49 benign and malignant breast tissues. PDGF-B expression was analyzed with respect to the expression of the proliferating cell nuclear antigen, as well as tumor grade, p53 overexpression, estrogen receptor, progesterone receptor, and c-erbB-2 expression. Expression of PDGF-B protein and mRNA was restricted to the breast epithelium and tumor cells except for scattered tissue macrophages. A strong correlation was found between increasing proliferating cell nuclear antigen indices and PDGF-B expression in both nonmalignant (P = 0.01) and malignant (P = 0.02) breast specimens. Decreased PDGF-B expression was found in postmenopausal atrophic breast tissue compared with normal breast tissue (P = 0.04). Within the subgroup of malignant tumors, no correlations were found between PDGF-B expression and tumor grade or p53 overexpression. In 16 of the malignant tumors evaluated for estrogen/progesterone receptor status and c-erbB-2 overexpression, no correlations with PDGF-B expression were found. Membranous PDGFR immunostaining was present within the fibroblastic cell population in all of the tissues examined but not in the nonmalignant breast epithelium. Six malignant specimens had detectable cytoplasmic expression of PDGFR. There was no correlation between this PDGFR expression and proliferating cell nuclear antigen indices, but a correlation was noted between increasing estrogen receptor expression and PDGFR cytoplasmic expression (P = 0.04). The results support a paracrine role for PDGF-B in malignant and benign breast epithelial cell proliferation.
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PMID:Expression of platelet-derived growth factor B-chain and the platelet-derived growth factor receptor beta subunit in human breast tissue and breast carcinoma. 778 Sep 88

We have studied the in vitro biological activities and mechanism of action of 1,25-dihydroxyvitamin D3 (1,25D3) and four potent 1,25D3 analogues [20-epi-22oxa-24a,26a,27a-tri-homo-1,25(OH)2D3 (KH 1060); 20-epi-1,25(OH)2D3; 1,25(OH)2-16ene-D3; and 1,25(OH)2-16ene-23yne-D3] on proliferation and differentiation of estrogen receptor-negative (MDA-MB-436, BT-20, SK-BR-3, and MDA-MB-231), estrogen receptor-weakly positive (BT474), and estrogen receptor-positive (MCF-7) breast cancer cell lines. Dose-response studies showed that KH 1060 was the most potent analogue, because it was able to induce differentiation in all seven breast cancer cell lines (measured by lipid staining) and to suppress more than 50% clonal proliferation (ED50) at 10(-10) M in all cell lines, except MDA-MB-436 and BT-20. To explore how these compounds mediated antiproliferative actions, their effects on the cell cycle, on expression of bcl-2 and p53, and on apoptosis were assessed. Five of six cell lines have a mutant p53 gene, whereas MCF-7 has wild-type p53. Immunohistochemical staining showed that the p53 protein was predominantly localized in the nucleus in each of the breast cancer cell lines except for MCF-7, which expressed the protein predominantly in the cytoplasm. After incubation with KH 1060 (3 days; 10(-7) M), expression of bcl-2 protein as determined by immunohistochemical localization was markedly decreased in BT-474, MCF-7, and MDA-MB-231; these same cells were profoundly inhibited in their clonal proliferation and arrested in the G0/G1 phase of the cell cycle when cultured with KH 1060. In contrast, BT-20 and MDA-MB-436 cells that were refractory to the antiproliferative effect of KH 1060 (ED50 < 10(-6) M) had no down-regulation of their bcl-2 expression and no cell cycle changes after exposure to KH 1060. MCF-7 showed morphological changes and DNA fragmentation, indicative of apoptosis after 48 h incubation with KH 1060 (10(-6) M), during which time p53 protein accumulated in the nucleus and decreased in the cytoplasm. In contrast, no apoptosis was detected in three other breast lines (MDA-MB-231, SK-BR-3, and BT-474) that had a mutated p53. In conclusion, the data indicate that KH 1060 is an extremely potent 1,25D3 analogue inducing differentiation of all six breast cancer lines and potently inhibiting clonal growth of four of them with concomitant decreased bcl-2 and cell cycle arrest at G0/G1.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:20-epi-vitamin D3 analogues: a novel class of potent inhibitors of proliferation and inducers of differentiation of human breast cancer cell lines. 779 9

Sixty-six unselected breast cancers were analyzed in cytologic smears and histologic sections for the expression of Ki-67, proliferating cell nuclear antigen (PCNA), estrogen receptor protein (ERP), and p53 protein using a standard immunochemical method. The results, expressed as both positive cases and labelling index (LI), were compared with clinical and pathobiological variables. Ki-67 and PCNA immunostaining was seen in all cases, whereas ERP was detectable in 46/63 cases and p53 protein in 20/66 cases. The expression of these markers was generally lower in cytology than in histology, though the differences were not statistically significant. PCNA-LI and Ki-67-LI were closely correlated (P < 0.001), the mean PCNA:Ki-67 ratio being 0.92 +/- 0.57. Occasional discrepancies, however, were found. PCNA and Ki-67 expression was associated with an increase in histologic grade and a decrease in ERP content of tumors, whereas p53 was statistically associated with no clinical or pathobiological variables. The data suggest that proliferative activity and oncogene overexpression may be reliably evaluated in breast cancer by FNA cytology, though PCNA is not a suitable indicator for cell proliferation. The results do not resolve the issue as to whether immunostaining for p53 protein constitutes a dedifferentiation product of the tumor, or is a fundamental aspect of the malignant progression. Survival studies in a larger series of tumors are thus needed to elucidate this point.
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PMID:Expression of proliferating cell nuclear antigen, Ki-67 antigen, estrogen receptor protein, and tumor suppressor p53 gene in cytologic samples of breast cancer: an immunochemical study with clinical, pathobiological, and histologic correlations. 781 60

Quantitative imbalance in chromosomal material relative to the normal diploid situation is the most conspicuous genetic change in breast tumors, affecting virtually all chromosomes in varying frequencies. This imbalance is reflected by deviant DNA stemlines observed in DNA flow cytometry analysis, by numerical chromosome abnormalities in karyotype analysis and by loss of heterozygosity in DNA polymorphism studies. Gene amplification might be caused by the same genetic mechanisms that cause these chromosomal abnormalities [134]. The number of known genes for which there is now good evidence for their role in the development of breast cancer is still limited, and basically restricted to TP53 and ERBB2. Clearly, the estrogen receptor, not discussed here, can be conjectured to be of importance in breast cancer development, yet the significance of the reported sequence variants [157] for hormone-independent growth is presently undetermined [158]. For many others, such as MYC, CCND1, EMS1, EGF, RB1, NME, DCC and prohibitin, the evidence is still largely circumstantial, or obtained only by in vitro studies on breast cancer cell lines. In many cases of chromosomal imbalance and certainly those affecting whole chromosomes or chromosome arms, it is unclear what their effect on tumor growth will be, because multiple potential candidate genes are located in the affected region. In addition, it is obvious that multiple chromosomes are affected simultaneously in a single tumor, but that the total set of chromosome changes varies in different tumors. This intra- and intertumor heterogeneity of chromosome involvement suggests that an unknown number of the observed abnormalities are not important for tumor development, but merely result from genetic instability. On the other hand, there is accumulating evidence, particularly from flow cytometry and allelotype studies reviewed here, to suggest that the genetic evolution associated with tumor development and progression does reach a stage of equilibrium despite the presence of extensive tumor heterogeneity. The number of genetic events found per tumor raises the question whether each event of heterozygosity loss represents the second step in the inactivation of a tumor suppressor gene. Also, LOH observed with polymorphic markers can sometimes be interpreted as allelic copy number gain instead of loss. Possibly, some of these allelic imbalances contribute to the tumorigenic process simply because they create a dosage effect in certain gene products [2]. This supposes that the sole presence of allelic imbalance at certain chromosomes is sufficient to provide selective growth advantage in certain cases.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Somatic genetic changes in human breast cancer. 781 70

A series of 200 breast carcinomas was investigated on frozen sections using PAb 1801 p53 monoclonal antibody and streptavidin biotin peroxidase complex. Densitometric analysis of the immunoprecipitates was assessed by processing digitized microscopic images. p53 was observed in the nucleus of 48% of the tumors. Some tumors (14 of 91) tested in parallel on paraffin sections were negative, although positive on frozen sections. Image analysis showed that the surfaces positive with anti-p53 and the staining intensity were decreased (P < .01) on paraffin sections. The p53 tumor expression was independent of patient age, tumor size, axillary lymph node status, HER-2/neu and cathepsin D expression, and nuclear morphometric parameters. However, p53 correlated with high histological grade (P < .01), lack of estrogen receptor (ER) (P = .0015) and progesterone (PR) (P = .0065) antigenic sites, pS2 detection (P = .03), high Ki-67 immunoreactivity (P = .018), large silver-stained nucleolar organizer region (AgNOR) nuclear surface ratio (P < .02), and degree of hyperploidy (P < .03), and was more often observed in the comedocarcinomas. The results suggest that p53 expression in breast carcinomas is not a totally independent prognostic indicator and that the clinical relevance and prognostic significance of p53 expression in breast carcinomas can be reliably assessed provided that the procedures are standardized, particularly with regard to the use of frozen sections and image analysis processing of the immunodetection.
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PMID:p53 quantitative immunocytochemical analysis in breast carcinomas. 786 46

The authors studied the role of 70-Kd heat shock protein (HSP70) in the progression of breast cancer by examining the correlation between the expression of HSP70 and epidermal growth factor receptor, c-erbB-2, p53, and estrogen receptor in 124 cases of invasive primary human breast cancers. Positivity of an anti-HSP70 monoclonal antibody, C92, was closely associated with the elevation of estrogen receptor (P < .008), whereas it inversely correlated with the expression of p53 (P < .01). In addition, the expression of HSP70 correlated inversely with the expression of epidermal growth factor receptor, although the correlation was not statistically significant (P = .06). These results suggest that the expression of HSP70 plays a role in the progression of human breast cancer.
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PMID:Correlation of heat shock protein 70 expression with estrogen receptor levels in invasive human breast cancer. 790 91

Fine needle aspirates (FNA) from 106 high-risk women and 25 low-risk women were evaluated for overexpression of estrogen receptor (ER), epidermal growth factor receptor (EGFR), mutant p53, and HER-2/neu by immunocytochemistry, and for aneuploidy by image analysis. Aspirates were also classified cytologically as normal, apocrine metaplasia, epithelial hyperplasia (EH), or dysplasia. High-risk women were those with a first-degree relative with breast cancer (76%), precancerous breast disease (26%), prior cancer of the contralateral breast (9%), or multiple abnormalities (11%). Low-risk women had none of the above risk factors, nor a prior breast biopsy or clinical evidence of fibrocystic disease. The median 10-year Gail risk for the high-risk group was 4%, compared to 0.7% for the low-risk group. There were significant differences (p < 0.01) between high- and low-risk women in the prevalences of hyperplasia (55% versus 12%), dysplasia (19% versus 0%), aneuploidy (32% versus 0%), overexpressed EGFR (32% versus 4%), and overexpressed p53 (29% versus 4%). The prevalence of multiple biomarker abnormalities was also greater in high-risk than in low-risk women (28% versus 0%; p < 0.01). Four percent (4%) of FNAs from high-risk women with normal cytology, 29% of aspirates with hyperplastic cytology, and 60% of those with dysplasia were associated with two or more biomarker abnormalities. The differences in the prevalence of multiple biomarker abnormalities among various cytologic categories were statistically significant (p = 0.02, normal versus EH; p = 0.02, EH versus dysplasia; p < 0.01, normal versus dysplasia).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biomarker and cytologic abnormalities in women at high and low risk for breast cancer. 791 61


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