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 insulin receptor (IR), a ligand-activated tyrosine kinase, is present in breast cancers, but its relationship to patient survival is unknown. The IR was measured in 584 tumor specimens from patients with node-negative breast carcinoma by frozen-section immunohistochemistry and light microscopy. The immunostaining signal was quantitated in relation to both the staining intensity and the proportion of positive malignant epithelial cells. Analyses indicated that patients with tumors with undetectable IR content in malignant epithelial cells (260 cases) had a relatively lower predicted 5-year disease-free survival (DFS) (69% +/- 3%) than did patients with tumors with detectable IR content (324 cases; DFS 76% +/- 3%, p = .032). The significance of IR content in these breast malignant epithelial cells was then analyzed along with patient age, tumor size, progesterone and estrogen receptor status, p53 accumulation, and S-phase. Multivariate analysis of these data revealed that after adjustment for these other variables, IR content was the strongest independent predictive factor for DFS (relative risk = 1.73, p = .005). Interestingly, in a small subset of patients with very high IR content (n = 62), DFS was decreased. These data indicate that IR content in node-negative breast cancers is a significant major predictor of reduced DFS. Moreover, they raise the possibility that the measurement of IR content might provide important information concerning breast cancer biology.
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PMID:Insulin receptor expression and clinical outcome in node-negative breast cancer. 939 18

We examined the association between mutation of the p53 gene and survival in a large cohort of breast cancer patients. Using a rapid, non-isotopic single-strand conformation polymorphism (SSCP) method we screened for mutations in exons 4-10 of the p53 gene in 375 primary breast cancers from patients with a median follow-up of 57 months. Mutations were found in 19% of tumours. Statistically significant associations were found between p53 mutation and histological grade, hormone receptor status, ploidy and S-phase fraction. No association was found between p53 mutation and axillary lymph node involvement, histological type, tumour size, vascular invasion or patient age. In univariate survival analysis, p53 mutation was strongly associated with poor prognosis. This was maintained in the lymph node-negative and hormone receptor-positive patient subgroups. In multivariate analysis, p53 mutation was associated with poor survival independent of lymph node status, estrogen receptor status and S-phase fraction. Our results demonstrate the feasibility of using a rapid and simple polymerase chain reaction-SSCP screening procedure to detect p53 gene mutation in breast cancer for the provision of prognostic information.
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PMID:Detection of p53 gene mutation by rapid PCR-SSCP and its association with poor survival in breast cancer. 942 63

Patients with primary breast carcinoma with one to three axillary lymph node metastases but without distant metastases (n1-3) in Japan have been shown to have a 10-year disease-free survival rate of > 60%. It would be reasonable to divide n1-3 Japanese breast cancer patients into groups with high- or low-risk for recurrence and to consider post-operative adjuvant therapy. In the present study, we analyzed 228 consecutive Japanese patients with n1-3 breast cancer who underwent radical mastectomy and were followed up for a median time of 11.0 years. The expression of bcl-2, p53 and c-erbB-2 proteins in the primary tumors was examined immunohistochemically and their prognostic roles were also analyzed along with conventional clinicopathologic indicators. bcl-2 expression was correlated with positive estrogen receptor status and inversely correlated with p53, c-erbB-2 and histologic grade. Univariate analysis showed that bcl-2, p53 and c-erbB-2 expression were prognostic indicators of the patient's group as well as node status, histologic grade, tumor size, age at diagnosis, menopausal status and estrogen receptor status. Cox's regression analysis demonstrated that the number of nodes involved, menopausal status, p53 and bcl-2 were independent predictors for overall survival and that histologic grade and the number of nodes involved were independent predictors for disease-free survival. These results suggest that bcl-2 expression in combination with p53 and c-erbB-2 expression, the number of lymph node metastases, histologic grade and menopausal status are useful in selecting subgroups of n1-3 breast cancer patients with good or poor prognoses.
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PMID:Prognostic indicators for breast cancer patients with one to three regional lymph node metastases, with special reference to alterations in expression levels of bcl-2, p53 and c-erbB-2 proteins. 943 97

In tumors, resistance to chemotherapeutic drugs that alkylate the O6 position of guanine correlates with the levels of the DNA repair protein, O6-alkylguanine DNA alkyltransferase (AGT). The expression of AGT gene in human breast tumors was evaluated at the level of the single cell, to better understand the distribution of alkylation resistant cells within the tumor. Compared to normal breast ductal cells, the level of AGT expression in the breast tumor cells increased 2-fold. There was no significant association between AGT expression and tumor grade and metastatic malignancy. The up-regulation of AGT was not directly linked to the expression of cyclins D1 and D3, estrogen receptor, p53 and c-erbB-2, genes involved in cell cycle regulation and tumor growth. The elevated expression of AGT in human breast ductal carcinoma cells appeared to be a general characteristic of breast tumors, and suggests that prior treatment with analogs of O6-alkylguanine that inactivate AGT protein, should render the AGT expressing tumor cells sensitive to drugs that alkylate O6-guanine.
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PMID:Expression of the O6-alkylguanine-DNA alkyltransferase gene is elevated in human breast tumor cells. 949 26

Recent studies have shown that chromosome 8p21-22 is the main site of frequent loss of heterozygosity (LOH) in breast cancers. However, the detailed molecular analysis of chromosome 8 so far in breast cancer has been variable. Most of the literature pertaining to LOH in breast cancer is mainly on short arm of chromosome 8. In the present study, we have examined LOH on both short and long arm of chromosome 8 using fifteen different polymorphic DNA markers in microdissected samples of normal breast epithelium and carcinoma from the same patients. For this purpose, DNA was extracted from the microdissected normal and tumor cells of 66 breast cancers, amplified by PCR and analyzed for LOH on chromosome 8 using fifteen different polymorphic DNA markers (D8S264, D8S298, D8S535, D8S255, D8S1098, D8S589, D8S567, D8S591, D8S285, D8S1102, D8S1763, D8S260, D8S530, D8S1772, and D8S1844). Expression of estrogen receptor, progesterone receptors, and p53 antigens was determined by immunohistochemistry using specific monoclonal antibodies. The results of this study suggest that LOH on chromosome 8 was identified in 40 of 66 cases (61%) with at least one marker. Three distinct regions of loss detected were: i) at 8p12, at loci between D8S535 and D8S255; ii) at 8p11, on loci D8S567, D8S591, D8S285, and D8S1102; iii) at 8q11-12, on loci D8S1763, D8S260 and D8S530. We found 45% (30 out of 66 informative cases) of the tumors showed LOH at 8p12; 52% (34 out of 66 informative cases) had LOH at 8p11; and 39% (26 out of 66 informative cases) had LOH at 8q11-12. Deletion at 8q11-12 was significantly correlated with the grade of the breast cancer specimens. Moderate to poorly differentiated specimens had higher incidence of LOH at 8q11-12 as compared to well differentiated specimens. Deletion at 8p12 and 8p11 was significantly higher in clinical stages III and IV of breast cancer tissues as compared to stage I and II cases. Tissues with lymph node involvement showed higher incidence of LOH at 8p12 as compared to the tissues with no lymph node involvement. There was no correlation of LOH at these loci with either the age of the patients, tumor size, BrdU labeling index, expression of estrogen receptor, progesterone receptor, and p53 in breast cancer specimens. These experiments, for the first time, report multiple sites of LOH on chromosome 8 in human breast cancer, and these deletions have differential correlation with clinical parameters of breast cancer samples.
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PMID:Multiple sites of loss of heterozygosity on chromosome 8 in human breast cancer has differential correlation with clinical parameters. 949 40

The bcl-2 family of proteins includes some important regulators of apoptosis. Among these, bcl-2 and bcl-xL prevent cells from entering apoptosis, whereas bax and bcl-xS can induce cell death. Alterations in the control of this process can lead to a decrease in cell death, thus contributing to neoplastic growth. Diminished susceptibility to chemotherapy has also been attributed, in in vitro systems, to alterations in the levels of bcl-2, bax, or bcl-x. We analyzed the expression of bcl-2, bax, bcl-xL, and bcl-xS in normal and neoplastic ovarian tissues by reverse transcriptase-PCR and Western blotting. The RNA and protein levels were significantly correlated for all genes. Interestingly, the levels of these genes in normal and neoplastic tissues were significantly different: bcl-2 was higher in normal tissue (P < 0.002), whereas bax and bcl-xL were higher in carcinoma (P < 0.018 and P < 0.030, respectively). bcl-xS was present at low levels in 83% of neoplastic samples and was undetectable in normal tissue. Reverse transcriptase-PCR analysis of 74 tumors showed no major correlation with clinicopathological parameters or with response to chemotherapy. Only bax and bcl-xL were correlated with progesterone receptor levels (n = 29, r = +0.44, P < 0.0189, and r = -0.40, P < 0.035, respectively). No correlation was found with estrogen receptor levels or with p53 immunostaining. Our data indicate that the regulation of the bcl-2 family of proteins differs between normal and neoplastic ovarian tissues. Moreover, the modulation of these genes in ovarian carcinoma is different compared to other tissues; therefore, tissue specificity is very important in regulation of the bcl-2 family of proteins.
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PMID:bcl-2, bax, bcl-XL, and bcl-XS expression in normal and neoplastic ovarian tissues. 951 44

Core needle biopsies (CNB) are often used for the diagnosis of breast lesions. In some breast cancer patients, e.g., those treated with preoperative chemotherapy, the CNB specimen might be the only pretreatment tissue sample available for studies of prognostic and predictive markers. Our purpose was to evaluate whether marker studies performed on CNB specimens accurately reflect the marker status of the tumor. Immunostaining for five commonly used prognostic and predictive markers was performed on both CNB and subsequent excision specimens from 56 consecutive patients who had a CNB with carcinoma followed by excision of the tumor. None of the patients received radiotherapy or chemotherapy between the CNB and the excision. Paraffin sections of the CNB and excision specimens were immunostained for bcl-2, estrogen receptor (ER), c-erbB-2, and p53. These markers were scored as positive or negative. Microvessel density (MVD) was scored as a continuous variable on sections immunostained for Factor VIII-related antigen by calculating the average number of microvessels in three 224x fields of highest tumor vascularity ("hot spots"). Immunostaining results for bcl-2, ER, c-erbB-2, and p53 on the CNB and the corresponding excision specimens were 100% concordant. Although there was significant correlation between MVD on the CNB specimens and the corresponding excisions (r = 0.507, P = 0.0002), the mean MVD on the CNB and corresponding excision specimens differed by more than 10% in 85.7% of cases, with differences ranging from 4.3 to 233.3%. MVD was higher in the CNB than in the excision specimens in 30 (61.2%) of 49 cases. In conclusion, in all of the cases studied, accurate results for the dichotomously scored markers bcl-2, ER, c-erbB-2, and p53 were obtained on CNB specimens. In contrast, in most cases, MVD, which was scored as a continuous variable, could not be reliably assessed on the CNB specimen.
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PMID:Do prognostic marker studies on core needle biopsy specimens of breast carcinoma accurately reflect the marker status of the tumor? 952 72

We have discovered a new, nonsteroidal, potent estrogen agonist/antagonist, CP-336,156. CP-336,156 binds selectively and with high affinity to the human estrogen receptor-alpha with a half-inhibition concentration of 1.5 nM, which is similar to that seen with estradiol (4.8 nM). When given orally to immature (3-week-old) female Sprague-Dawley rats for 3 days at doses of 0.1, 1.0, 10, or 100 microg/kg x day, unlike 17alpha-ethynyl estradiol, CP-336,156 had no effect on uterine wet or dry weight. Similarly, no uterine hypertrophy was observed in aged (17-month-old) female rats treated (p.o.) with CP-336,156 at 10 or 100 microg/kg x day for 28 days. We also found that CP-336,156 decreased total serum cholesterol and fat body mass and had no effect on lean body mass in these aged female rats. In 5-month-old ovariectomized (OVX) Sprague-Dawley female rats, CP-336,156 completely prevented OVX-induced increases in body weight gain, total serum cholesterol, and serum osteocalcin at doses between 10 and 1000 microg/kg x day after 4 weeks. At these doses, CP-336,156 completely prevented OVX-induced bone loss and inhibited the increased bone turnover associated with estrogen deficiency in lumbar vertebrae, proximal tibiae, and distal femora. Similar to estrogen, CP-336,156 induced apoptosis and p53 expression with a concomitant decrease in the number of tartrate-resistant acid phosphatase-positive multinuclear cells in rat bone marrow cell cultures in vitro, suggesting that the induction of apoptosis may be a mechanism for the estrogenic activities of CP-336,156 in bone. In summary, CP-336,156 is a new, orally active, nonsteroidal, potent estrogen agonist/antagonist that has similar effects in bone as estradiol but without the uterine-stimulating effects associated with estradiol in rats.
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PMID:Effects of CP-336,156, a new, nonsteroidal estrogen agonist/antagonist, on bone, serum cholesterol, uterus and body composition in rat models. 952 95

Predisposition to breast cancer has been attributed to mutant BRCA1 alleles whereas no BRCA1 mutation has been described yet in sporadic breast tumours. As an initial characterization of the regulation and function of the BRCA1 gene in sporadic breast cancer, we have compared the expression of BRCA1 in thirty-five paired tumour specimens versus their corresponding adjacent normal tissue. We found two- to five-fold reduced BRCA1 expression levels in tumour specimens as compared to normal tissue. Decreased BRCA1 expression was significantly associated with loss of heterozygosity (LOH) at the BRCA1 region, as well as with negative estrogen receptor (ER) status. Our results offer an alternative explanation of how BRCA1 could play an important role in sporadic breast cancer, not via mutations in coding sequences but due to transcriptional disregulation. Decreased BRCA1 mRNA may be caused due to loss of gene copies, deletions of regulatory elements in the BRCA1 promoter or failure of transcriptional regulation by estrogen receptors. We also investigated possible relationships between BRCA1, p53, mdm-2 and p21(WAF1/CIP1) at the expression level. p53 expression was unaffected in almost all the specimens, mdm-2 was overexpressed in 18/35 specimens while 21/35 overexpressed p21. Samples exhibiting reduced BRCA1 levels simultaneously overexpressed both p21 and mdm-2, showing that BRCA1, at certain levels, even reduced up to 2.7-fold, is functional and sufficient to upregulate p21, when p53 activity is inhibited by its negative regulator, the mdm-2. On the contrary, specimens exhibiting more than 2.7-fold reduced BRCA1 levels, overexpressed p21 while mdm-2 expression was normal, allowing us to speculate that p21 transcriptional activation is due to p53 activity, in cases with dramatically decreased BRCA1 expression. Our findings provide evidence, indicating that BRCA1 might affect cell cycle regulation and loss of BRCA1 function due to decreased expression leads to cell cycle arrest, through p53 and p21 genes.
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PMID:Decreased BRCA1 expression levels may arrest the cell cycle through activation of p53 checkpoint in human sporadic breast tumors. 953 86

To validate the prognostic value of the determination of p53 expression, intratumoral microvessel density (IMD) (a measure of angiogenesis), and the conventional features, we studied 531 patients operated of breast cancer (271 node-positive and 260 node-negative), with a median follow-up exceeding 6 years. IMD was assessed by using the anti-CD31 antibody to identify the microvessels. p53, estrogen receptor (ER) and progesterone receptor (PgR) were determined by immunocytochemistry using the antibodies PAb1801, H-222 Sp2y and KD-68, respectively. The prognostic value of the markers was analyzed by univariate and multivariate statistical analyses. In the overall series p53 expression, IMD, nodal status, ER and PgR were statistically significant prognostic indicators for both relapse-free survival (RFS) and overall survival (OS) in the final multivariate model. Likewise, tumor size and menopausal status were significant prognostic indicators for RFS and OS, respectively. In the subgroup of node-negative patients who did not receive adjuvant therapy only p53, IMD, and tumor size were statistically significant in multivariate analysis. In the subgroup of node-positive patients treated with adjuvant chemotherapy, IMD, the number of involved nodes and PgR were statistically significant in multivariate analysis. In the subgroup of node-positive patients treated with adjuvant tamoxifen, IMD and ER (and the number of involved nodes, only for OS) were statistically significant for both RFS and OS in the final multivariate model. Different markers played a diverse prognostic role in the diverse subgroups studied. Angiogenesis was the sole marker which retained prognostic value in all the sub-groups analyzed. p53 retained significance only in the subgroup of node-negative patients, whilst ER and PgR were statistically significant in the subgroups of node-positive patients treated with adjuvant hormone therapy or chemotherapy, respectively.
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PMID:Prognostic significance of p53, angiogenesis, and other conventional features in operable breast cancer: subanalysis in node-positive and node-negative patients. 953 38


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