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)

The prognostic value of p53 protein accumulation in breast cancer, especially as detected by methods other than immunohistochemistry, has not been established unequivocally. A sensitive immunofluorometric assay of p53 protein employing DO-1 and CM-1 antibodies was used in this study to assay extracts of 171 breast carcinomas from northern Italy. p53 over-expression, demonstrated in 36 (21%) tumours, was associated with lack of oestrogen receptor (ER) expression but was not related to patient age, stage, lymph node status, tumour size, histologic type, grade or progesterone receptor (PR) expression status in contingency tables. An increased risk for cancer relapse of p53-positive patients compared to p53-negative patients was determined using multivariate Cox regression analysis, which also showed that p53 protein over-expression was an independent predictor of reduced disease-free survival in node-positive and ER+ patients but not in node-negative or ER- individuals. The equivalent analysis for assessing the impact of p53 status on overall survival was not statistically significant, possibly reflecting the short patient follow-up. Our results suggest that an immunoassay of p53 protein, applicable to cytosolic extracts prepared for steroid hormone receptor analyses, may provide information for breast cancer prognosis.
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PMID:Immunofluorometrically determined p53 accumulation as a prognostic indicator in Italian breast cancer patients. 958 29

IIB-BR-G is an undifferentiated, highly heterogeneous, hormone receptor negative human breast cancer cell line previously established in our laboratory from a patient's primary tumor. An in vitro growing cell line (IIB-BR-G) and a xenotransplanted tumor growing in nude mice (IIB-BR-G(NUDE)) were derived. To further characterize these systems, immunocytochemical analysis was performed for differentiation antigens (PEM 200 kDa, CEA, NCA 90 kDa), blood-group related antigens (Le(x), sTn), oncogenes and tumor suppressor gene products (Her-2/neu protein, p53), metastasis-related cathepsin D and CD63/5.01 Ag, and the chemokine monocyte chemotactic protein 1 (MCP-1). Expression of markers was heterogeneous in these different systems. Previously reported karyotypic analysis has shown extensive chromosomal alterations including double min. Searching for oncogene amplification, we detected augmented copy number of c-myc and c-fos, the last one with two rearranged fragments. No amplification was found for c-erbB-2 in the cell line or in IIB-BR-G(NUDE), although this oncogene was amplified in the patient's primary tumor DNA. The differences observed between the patient's tumor, the cell line and the IIB-BR-G(NUDE) tumors are probably due to clonal expansion of cell variants not present in the original tumor. Electron microscopy of IIB-BR-G growing cells revealed epithelial characteristics with abundant dense granules, presumably secretory, distributed all over the cytoplasm and great nuclear pleomorphism. In vitro, IIB-BR-G cells showed a significant number of invading cells by Matrigel assay. After nearly 40 sequential subcutaneous passages of the original xenograft through nude mice, 80% of recipients developed spontaneous metastases, primarily to the lung and lymph nodes. Since this experimental model allowed to analyze changes produced in cancer cells from the primary tumor during adaptation to in vitro and in vivo growth, our results provide novel insights on the behaviour of hormone independent metastatic breast cancer.
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PMID:The human breast cancer cell line IIB-BR-G has amplified c-myc and c-fos oncogenes in vitro and is spontaneously metastatic in vivo. 962 Apr 46

Although cytotoxic chemotherapy is widely used in advanced breast cancer, there are no powerful predictors for the therapy response. Because topoisomerase IIalpha (Topo IIalpha) is the molecular target for the anthracycline class of anti-cancer drugs, we compared the immunocytochemical assay of Topo IIalpha with other biomarkers in the prediction of clinical response to Topo II inhibitor chemotherapy. Fifty-five patients with advanced breast cancer were treated with a single cytotoxic drug, Topo II-inhibitor, epirubicin (30 mg m(-2) weekly up to 1000 mg m(-2)), as first line cytotoxic chemotherapy. Objective response to treatment was analysed according to UICC criteria. The predictive value of Topo IIalpha expression, c-erbB2 oncoprotein, p53 tumour-suppressor protein, oestrogen (ER) and progesterone receptor (PR), S-phase fraction and DNA ploidy were analysed from representative formalin-fixed paraffin-embedded primary tumour samples. The proportion of Topo IIalpha-positive cells (Topo IIalpha index) failed to predict response to epirubicin therapy. Mean Topo IIalpha scores in 29 responding patients were similar when compared with those with no change in disease progression (n = 13) and those with progressive disease (n = 13) (14.9% +/- 11.4% vs 15.5% +/- 7.6% vs 17.3% +/- 13.2%, not significant). Among the other biomarkers tested, overexpression of c-erbB2 oncoprotein and hormone receptor negativity were significantly associated with poor response. Response rate in patients with c-erbB2-overexpressing tumours was 32% compared with 65% in patients with no c-erbB2 overexpression (P = 0.0058). Accordingly, the response rate for ER-positive patients was 67% compared with 26% in ER-negative patients (P = 0.0021). Although both negative ER status and c-erbB2 overexpression are associated with high Topo IIalpha expression in breast cancer, step-wise logistic regression analysis showed that ER and c-erbB2 were associated with therapy response independent of Topo IIalpha expression. Histological grade, p53, DNA-ploidy, tumour proliferation rate (S-phase fraction), stage of the disease at diagnosis, age of the patient, previous anti-oestrogen therapy or site of metastasis did not predict the response to epirubicin therapy. In conclusion, despite extensive in vitro evidence, expression of Topo IIalpha is unlikely to predict the response to Topo II inhibitor chemotherapy in advanced breast cancer. Among the prognostic biomarkers, overexpression of c-erbB2 oncogene and negative ER may have predictive value in epirubicin therapy in patients with advanced breast cancer.
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PMID:Predictive value of topoisomerase IIalpha and other prognostic factors for epirubicin chemotherapy in advanced breast cancer. 964 44

Controversy continues regarding the prognostic utility of detection of p53 gene abnormalities in node-negative breast cancer. To resolve this, we used a rapid and nonisotopic PCR-single strand conformation polymorphism method to screen for mutations in exons 4-8 of the p53 gene in primary tumors from 422 node-negative breast cancer patients. The prevalence of p53 mutation in the exons tested was 18%. p53 mutation was significantly associated with several markers of poor prognosis including larger tumor size, high tumor grade, low hormone receptor content, increased expression of MIB-1 (Ki-67), amplification of the HER-2/neu oncogene, and accumulation of the p53 protein. After a median duration follow-up period of 74 months, the parameters of tumor diameter > or =20 mm, HER-2/neu oncogene amplification, and p53 mutation were found to be associated with a statistically significant shortened duration of disease-free and overall survival, but not the parameters of tumor grade, hormone receptor levels, or p53 expression. The poor prognosis associated with p53 mutation was observed primarily in patients with a tumor diameter of > or =20 mm. In multivariate analysis, p53 mutation was a risk factor for increased risk of recurrence and death from breast cancer independent of tumor size, hormone receptor levels, HER-2/neu amplification, and MIB-1 expression. We conclude that a relatively simple and rapid single strand conformation polymorphism method of determining p53 mutation status in node-negative breast cancers can provide independent prognostic information.
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PMID:Analysis of p53 gene mutation by polymerase chain reaction-single strand conformation polymorphism provides independent prognostic information in node-negative breast cancer. 967 32

The occurrence of p53, bcl-2 and heat shock protein (HSP) expression in ovarian tumours was examined and the correlation was investigated between the expression of these proteins and other disease parameters, including FIGO stage, histological subtype, tumour differentiation and steroid hormone receptor status. We analysed p53, bcl-2 and HSP expression in 100 smears of patients with epithelial ovarian carcinomas, 16 smears of patients with borderline malignancy and 20 smears of patients with benign ovarian neoplasms by using immunocytochemical techniques. There were 29 patients with stage I disease, 24 with stage II disease, 40 with stage III disease and seven with stage IV disease according to the FIGO classification. The sensitivities and specificities of bcl-2, p53 and HSP for malignancy were 53% and 40%, 43% and 80%, and 37% and 90%, respectively. HSP was statistically significantly associated with malignant rather than benign tumours. Significant association was also observed between bcl-2 and p53, and p53 and HSP. The association of HSP with malignant tumours is confined to the premenopausal group of patients and in this group by itself there is also a significant association between p53 and malignancy. HSP and p53 were associated with undifferentiated carcinomas, bcl-2 and p53 expression is reduced as disease stage progresses in serous carcinomas and bcl-2 expression is increased as disease progresses in endometrioid carcinomas. There was no significant association between bcl-2 and ER/PR status. In conclusion, HSP has a high specificity for malignant ovarian tumours, bcl-2 and p53 have only moderate to low sensitivity and specificity. Changes in the frequency of bcl-2 and p53 overexpression between FIGO I and FIGO III stage disease of different ovarian carcinomas indicate a different role of these substances in cellular survival mechanisms in different carcinomas. bcl-2 probably is associated with cell proliferation but not with differentiation.
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PMID:Expression of p53, bcl-2 and heat shock protein (hsp72) in malignant and benign ovarian tumours. 969 31

Tumor biological factors uPA, PAI-1, cathepsin D, S-phase fraction (SPF), MIB1 (Ki-67), p53, and HER-2/neu were assessed in 100 node-negative breast cancer patients. Their prognostic impact on disease-free (DFS) as well as overall survival (OS) was compared to that of traditional factors tumor size, grading, and steroid hormone receptor status. Antigen levels of uPA, its inhibitor PAI-1, and cathepsin D were determined in tumor tissue extracts by immunoenzymatic methods. SPF was determined by flow cytofluorometry, MIB1, p53, and HER-2/neu by immunohistochemistry in adjacent routinely formalin-fixed paraffin sections. Median follow-up in all patients still alive at time of analysis was 76 months. Univariate analysis determined PAI-1 (p = 0.0001), uPA (p = 0.0437), MIB1 (p = 0.0214), and SPF (p = 0.0248) as statistically significant prognostic factors for DFS. In contrast, tumor size, steroid hormone receptor status, grading, p53, HER-2/neu, and cathepsin. D failed to be of prognostic value. In multivariate analysis, including the statistically significant prognostic factors PAI-1, uPA, MIB1, and SPF, only PAI-1 (p = 0.0003, relative risk: 4.7) proved to be of independent statistical significance for DFS. Regarding OS, PAI-1 was the only statistically significant prognostic factor in univariate (p = 0.0001) as well as multivariate analysis (p = 0.0000, relative risk: 7.1). Thus, factors describing the invasive and metastatic capacity of tumor cells (uPA, PAI-1) and factors related to their proliferative activity (SPF, MIB1) provide valuable prognostic information in node-negative breast cancer patients.
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PMID:Prognostic impact of tumor biological factors on survival in node-negative breast cancer. 970 82

The polycyclic aromatic hydrocarbon (PAH), methylcholanthrene (MCA), is a well studied carcinogen and a teratogen. MCA and other PAH cause immune suppression of B cell and T cell responses in mice and MCA had been reported to induce thymus atrophy. Here we show that MCA treatment causes thymus atrophy in adrenalectomized mice and in C57BL/6 and DBA/2 mice which differ in aryl hydrocarbon receptor (AhR) expression. This indicates that MCA-mediated thymus atrophy is mediated, at least in part, by glucocorticoid hormone receptor- and aryl hydrocarbon receptor-independent mechanisms. Assay of thymocytes, both in situ and ex vivo, demonstrate that MCA induces thymocyte apoptosis. Apoptotic thymocytes can be found within or adjacent to thymic Mphi, suggesting rapid phagocytosis. Mice that are deficient in tumor necrosis factor-alpha receptor-1 or p53, or that overexpress bcl-2 are susceptible to MCA-mediated thymus atrophy.
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PMID:Methylcholanthrene causes increased thymocyte apoptosis. 971 Jan 56

We have analysed the expression of bcl-2 protein retrospectively in 34 primary male breast carcinomas (MBC), using the monoclonal antibody bcl-2 in formalin-fixed, paraffin-embedded tissues. Bcl-2 expression was compared with tumour clinicopathological features, sex steroid hormone receptors, DNA content, p53 immunoreactivity and cell proliferative activity assessed by counts of the argyrophilic nucleolar organizer regions (AgNORs), the monoclonal antibody PC10 against proliferating cell nuclear antigen and the monoclonal antibody MIB-1. Most (28, or 82.3%) of the 34 cases of MBC were bcl-2 positive. No association was found with clinicopathological features of the tumours, although bcl-2 tended to be more frequently expressed in small tumours (P=0.09) and in cases without necrotic areas (P=0.1). Nor was any association found with hormone receptor status, p53 immunoreactivity, DNA content, cell proliferative activity or patient survival. In multivariate analysis, only proliferative activity (expressed by AgNOR counts) and p53 immunoreactivity had independent prognostic significance. Our results indicate that MBC differs from FBC in that in MBC bcl-2 protein is not related to an oestrogen-dependent transcription pathway and bcl-2 alone is not sufficient to induce increased proliferation. These characteristics, together with the high prognostic value of cell proliferation and the lack of prognostic significance for hormone receptor status, support the hypothesis that MBC is biologically different from FBC.
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PMID:Bcl-2 expression in male breast carcinoma. 976 26

Patients with hereditary breast cancer (HBC) present at a young age with breast cancers that show adverse pathological characteristics such as high nuclear grade, negative hormone receptor status, and high proliferation indices. Surprisingly, the clinical course has been reported to be comparable or improved compared with patients with nonhereditary breast cancer (non-HBC). To determine whether there are any molecular markers that might help explain this paradox between pathologically aggressive neoplasms in patients with HBC and the lack of extreme clinically aggressive disease, we studied several molecular parameters in a group of 34 breast cancer patients with mutations in either the BRCA1 or BRCA2 tumor suppressor genes and compared them with a group of 20 breast cancer patients with non-HBC. In general, patients with HBC had tumors that were of higher nuclear grade, contained a higher population of proliferating cells, showed increased expression of DNA topoisomerase II-alpha (topo II-alpha), lacked hormone receptors, and were more likely to show immunopositivity for the p53 tumor suppressor gene. Additionally, tumors from patients with HBC showed a decreased angiogenesis compared with controls. The decreased angiogenesis and the elevated expression of topo II-alpha (an anticancer drug target) may, in part, explain the lack of correlation between clinical course and histological characteristics in patients with HBC.
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PMID:Pathobiologic characteristics of hereditary breast cancer. 978 55

Most studies are in favor of a prognostic relevance of p53 accumulation determined by immunohistochemistry in breast cancer, but negative results are not lacking. On a series of 1400 patients with lymph node-negative cancers treated with local-regional therapy alone until relapse and with a median follow-up of 10 years, we validated the prognostic relevance for overall relapse and death of p53 accumulation observed in a pilot study and analyzed its predictivity on different adverse events. p53 protein accumulation was immunocytochemically detected using PAb1801. The case series had also been previously characterized for hormone receptor content [estrogen receptors (ERs) and progesterone receptors (PgRs)] and for cell proliferation [[3H]thymidine labeling index ([3H]dT LI)]. p53 expression, considered as a dichotomous variable with a cutoff value of 5% positive cells, significantly predicted the occurrence of overall relapse, distant metastasis, and death with an interaction with cell proliferation. p53 accumulation, cell proliferation, and their interaction term, along with tumor size and patient age, retained a predictive role for overall relapse, and together with tumor size and PgR, also for overall survival. When considered as continuous variables, we observed that the hazard of metastasis increased linearly with the increase of [3H]dT LI and decreased linearly with the increase of ER and PgR. Conversely, the hazard increased with the increase of p53-positive cells only for tumors with a [3H]dT LI lower than 7.5%. In multivariate analysis, the same prognostic factors for distant metastasis were identified when the biomarkers were considered as continuous or dichotomous variables.
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PMID:Validation of p53 accumulation as a predictor of distant metastasis at 10 years of follow-up in 1400 node-negative breast cancers. 981 60


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