Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:B6E4X6 (mutant p53)
 3,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of p53-protein appears to be a common event in primary breast cancer. It has been proposed that the presence of elevated levels of this protein may be an independent prognostic factor and may be important for the ability of a tumor to metastasize. This study was performed to evaluate the influence of immunohistochemically detectable mutant p53-protein on metastasis-free survival of patients with breast cancer. Immunohistochemistry was performed on 117 paraffin-embedded biopsy specimens of consecutive patients with stage T1-T4 breast cancer, using a monoclonal antibody against p53 suppressor gene product. 29 (24.8%) specimens showed positive staining, whereas in 88 (75.2%) a negative staining reaction for p53 was found. Comparing time intervals to diagnosis of metastasis, using Kaplan-Meier curves, Log-Rank test revealed no significant differences in metastasis-free survival between p53 positive and negative patients (P = 0.32), whereas statistically significant differences were noted for tumor stage (P < 0.01), nodal status (P < 0.01), histological grading (P < 0.01) and estrogen receptor status (P = 0.03). Mutant p53-protein, as detected by immunohistochemistry in paraffin embedded tumor tissue, does not appear to influence metastasis-free survival in patients with breast cancer.
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PMID:Immunohistochemical detection of mutant p53-suppressor gene product in patients with breast cancer: influence on metastasis-free survival. 129 80

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

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

Nuclear accumulation of p53 protein is associated with a poorer clinical outcome in breast cancer patients. Heat shock protein 70 (hsp70) is a chaperone that binds to mutant p53 and consequently could regulate its accumulation or localization. The aims of this study were to determine if the prognostic significance of p53 accumulation was dependent on the type of antibody used for detection and whether hsp70 was associated with this accumulation. Node-negative breast tumors (n = 169) were examined by immunohistochemistry for nuclear p53, cytoplasmic or nuclear hsp70, and for p53 gene alteration by single-strand conformation polymorphism analysis. Frozen sections of pulverized breast tumors were stained with five p53 antibodies (240, 1801, 421, BP53-12, and CM1), a cocktail of both 240 and 1801, and the hsp70 antibody C92. Protein level was expressed as the sum of a proportion and intensity score (total 0, 2-8) with > or = 2 defined as positive staining. The cocktail 240/1801 gave the highest rate of positive staining (45%), followed by BP53-12 (35%), 1801 (27%), 240 (25%), CM1 (24%), and 421 (18%), with a high correlation between antibodies. Positive staining with each individual antibody or the cocktail was significantly associated with estrogen receptor and progesterone receptor negativity, age < 50, and high S-phase fraction. Only staining detected by the 240/1801 cocktail was associated with significantly worse overall survival; 85 versus 70% at 5 years for p53-negative compared to p53-positive tumors, respectively (P = 0.02). There was no association between nuclear or cytoplasmic hsp70 staining and accumulation of p53. Patients that were p53-negative/cytoplasmic hsp70-positive had a better overall survival than those that were p53-negative/cytoplasmic hsp70-negative. No other combination of p53 and hsp70 status could further define subsets of patients with a significantly different prognosis compared to p53 status alone. Tumors without a detectable p53 gene alteration by single-strand conformation polymorphism but with accumulated p53 protein did not have relatively increased levels of hsp70. We conclude that in node-negative breast cancer, the cocktail of two antibodies, 240/1801, resulted in the highest rate of positive staining and was most strongly associated with overall survival compared with either antibody alone or with the other individual antibodies. By immunohistochemistry, nuclear accumulation of p53 was not associated with cytoplasmic or nuclear hsp70 levels.
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PMID:p53 protein accumulation detected by five different antibodies: relationship to prognosis and heat shock protein 70 in breast cancer. 803 95

The immunohistochemical expression of the p53 gene protein was examined in a consecutive series of 143 cases of pure ductal carcinoma in situ (DCIS) of the breast. Expression of wild-type and/or mutant p53 protein was detected in 36 (25.2%) of the cases examined, as evidenced by positive nuclear staining with the monoclonal antibody DO 7. Thirty-four (35.8%) of the large cell cases showed p53 protein expression compared with two (4.1%) of the small cell cases (chi 2 = 15.3 [df = 1], P < .001). p53 Protein expression also was associated with an increased histologic degree of necrosis, with a nearly significant association of negative tumor estrogen receptor status and p53 protein expression. No significant association of p53 protein expression and c-erbB-2 protein expression was seen. Immunohistochemical expression of p53 protein is present in approximately 25% of DCIS cases and is confined almost exclusively to large cell DCIS, a morphologic subtype of in situ breast carcinoma thought to be more biologically aggressive. Expression of p53 protein may be important in the neoplastic progression of DCIS, reflecting the acquisition of p53 gene mutations in large cell DCIS cases. Therefore, p53 may be implicated in mammary tumor evolution from in situ to invasive disease.
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PMID:p53 protein expression in mammary ductal carcinoma in situ: relationship to immunohistochemical expression of estrogen receptor and c-erbB-2 protein. 809 18

Among 843 cases of breast cancer, p53 oncoprotein was detected by the monoclonal antibody (MoAb) Pab-1801 in only 13%. Low-grade carcinomas (tubular, mucinous, papillary, and invasive cribriform types) did not express p53 protein, but it was observed in 4.2% of infiltrating lobular carcinomas (6 of 140 cases) and 50% of pure medullary carcinomas (5 of 10 cases). In intermediate-grade neoplasms, no correlation was seen between p53 status and other putative determinants of a poor prognosis. The latter included high tumor stage, lymph nodal involvement, high growth fraction (as determined by labeling with the MoAb Ki-67), negative results for estrogen receptor (ER) and progesterone receptor (PR) proteins, and amplification of the c-erbB-2 oncogene product in the neoplastic cells. Ninety-nine of 640 (15.5%) cases of high-grade, invasive, ductal breast carcinoma, however, showed an inverse relationship between expression of p53 protein and positive results for ER/PR proteins and a direct correlation with large tumor size, Ki-67-determined growth fraction, and amplification of c-erbB-2 oncopeptide. All of the latter associations were highly significant statistically. The authors conclude that mutant p53 protein may serve a prognostic role in a subset of cases of invasive ductal mammary carcinoma.
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PMID:Relationship between p53 expression and other prognostic factors in human breast carcinoma. An immunohistochemical study. 837 28

Recent evidence has emphasized the importance of programmed cell death or apoptosis in the maintenance of tissue homeostasis and pathogenesis of tumors. This study, analyzed in breast cancer, investigates the significance of apoptosis in relation to the expression of p53 and bcl-2 proteins, tissue proliferation defined by Ki-67 expression, hormone receptors and tumor grade. The extent of apoptosis was defined by morphological criteria and the TUNEL (Tdt-mediated dUTP biotin nick end labelling) assay. Immunocytochemistry was performed for p53, bcl-2, estrogen receptor, progesterone receptor and Ki-67 expression. Mutant p53 protein was detected using a mutant specific ELISA. Immunoreactivity of p53 significantly correlated with the presence of mutant p53 protein detected by ELISA (r = 0.654, p = 0.00001). An inverse correlation was observed between bcl-2 expression and the extent of apoptosis (r = -0.33369, p = 0.01912). The extent of apoptosis directly correlated with p53 protein accumulation (r = 0.485, p = 0.00041), Ki-67 immunoreactivity (r = 0.435, p = 0.001), histopathological grade (r = 0.492, p = 0.0003), tumor size (r = 0.326, p = 0.023) and lymph node status (r = 0.287, p = 0.047). A direct correlation was also observed between p53 expression and Ki-67 immunoreactivity (r = 0.623, p = 0.0002). There was no statistically significant association between estrogen and progesterone receptor status and apoptosis. In addition, the TNM stage of the disease correlated with immunoreactivity of p53 (r = 0.572, p = 0.00012) and Ki-67 (r = 0.3744, p = 0.00818). Bcl-2, by inhibiting apoptosis, may cause a shift in tissue kinetics towards the preservation of genetically aberrant cells, thereby facilitating tumor progression. These results imply that rapidly proliferating tumors appear to have a high "cell turnover state" in which there may be an increased chance of apoptosis amongst the proliferating cells. The ability of apoptosis to also occur in the presence of mutant p53 protein suggests the existence of at least two p53-dependent apoptotic pathways, one requiring activation of specific target genes and the other independent of it.
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PMID:Spontaneous programmed cell death in infiltrating duct carcinoma: association with p53, BCL-2, hormone receptors and tumor proliferation. 977 89

A substantial portion of patients with estrogen receptor-positive breast cancer fail to respond to estrogen depletion or to the antiestrogen tamoxifen. The molecular changes that lead to tamoxifen resistance and estrogen-independent growth are unknown. To test the hypothesis that a p53 mutation could result in tamoxifen resistance and estrogen-independent growth, the MCF-7 cell line was transfected with p53 cDNA which was mutated at codon 179 (histidine to glutamine). MCF-7 is an estrogen receptor-positive, estrogen-dependent, tamoxifen-sensitive cell line with only wild-type p53. The presence of transfected mutant p53 cDNA was verified by the PCR, and overexpression of p53 protein was assessed by Western blotting. Five separate mutant-transfected clones were selected and tested in subsequent growth experiments. In monolayer culture, there was no consistent evidence of estrogen-independent growth or tamoxifen resistance in the mutant transfectants compared with vector-only controls or the parental cell line. In soft agar growth experiments, four of five mutant transfectants remained sensitive to tamoxifen in a dose-dependent manner. In the presence of wild-type p53, mutant 179 p53 protein does not result in estrogen-independent growth or tamoxifen resistance. These results do not exclude the possibility that other p53 mutational types could result in tamoxifen resistance, or that loss of the remaining wild-type allele may be necessary to result in this phenotype.
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PMID:p53 mutation and tamoxifen resistance in breast cancer. 981 13

Bcl-2 and Bax have been demonstrated to be associated with apoptosis in breast carcinoma, and the ratio between Bax and Bcl-2 seems to be an important determinant of cellular sensitivity to induction of apoptosis. However, little information is available on the relationship between Bcl-2, Bax and the proliferative activity of breast carcinoma. The purpose of this study was to investigate the significance of apoptosis-related genes bcl-2 and Bax and their correlation with expression of p53, tumor proliferation defined by MIB-1 expression and estrogen receptor status. Immunohistochemistry was performed to determine Bcl-2, Bax, p53, estrogen receptor (ER) and MIB-1 expression in paraffin-embedded tissues of 177 invasive breast cancers. Expression of the anti-apoptotic protein Bcl-2 was not correlated with the pro-apoptotic Bax. Bcl-2 immunostaining displayed a negative correlation with increasing histologic grade, p53 and MIB-1 (P < 0.0001, P < 0.05 and P < 0.0001, respectively) and a positive correlation with rising ER immunostaining (r = 0.305, P < 0.0001). Conversely, expression of the apoptosis-promoting protein Bax did not correlate with increasing histologic grade, p53, MIB-1 or ER status. Neither Bcl-2 expression nor Bax expression correlated with age, menopausal status, tumor size, histologic type or axillary lymph node status. These results imply that Bcl-2 is associated with good prognostic markers and the regulation of Bax is complex and does not necessarily correlate with mutant p53 status in breast cancers.
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PMID:Expression of Bcl-2, but not Bax, correlates with estrogen receptor status and tumor proliferation in invasive breast carcinoma. 1050 48

Recovery of p53 function in undifferentiated thyroid carcinoma cells carrying an altered p53 gene is able to modify cell tumorigenic properties. It is not known whether such an effect may also be achieved in thyroid cancer cells expressing wild-type p53, as in the majority of differentiated thyroid carcinomas. Effects of p53 transduction in a thyroid carcinoma cell line (FRO) exhibiting a wild-type endogenous p53 gene, in comparison to a cell line (WRO) exhibiting mutant p53, were investigated by using an inducible chimeric construct containing human p53 complementary DNA fused to the ligand binding domain of the estrogen receptor (p53ER). FRO cells were unaffected by exogenous p53 expression in terms of both proliferation and viability. On the contrary, p53 reexpression in WRO cells containing hemizygous mutated p53 allele caused a strong growth inhibition due to cell accumulation in the G1 phase of the cell cycle. In addition, exogenous p53 did not influence FRO cell behavior in response to TSH treatment or modify cell resistance to the chemotherapeutic agent, doxorubicin. Our results indicate that exogenous expression of wild-type p53 affects thyroid tumorigenic properties only in cells carrying an altered p53, whereas it is ineffective in cells expressing wild-type p53 activity. Therefore, the endogenous p53 status seems to be a major determinant for the effectiveness of a p53-based gene therapy for thyroid cancer.
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PMID:Effects of exogenous p53 transduction in thyroid tumor cells with different p53 status. 1063 3


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