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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using a panel of ten polymorphic markers, we examined the frequency of loss of heterozygosity (LOH) on chromosome 17 in 55 sporadic ovarian tumours. LOH on 17p and 17q was observed to be 50% and 62% respectively. LOH at D17S5 was detected in 24/36 (67%) of malignant cases and in 19/43 (44%) at TP53; the marker D17S855 intragenic to the BRCA1 gene showed allele loss in 50% (20/40) cases. The data presented here suggest that loss of the whole chromosome 17 is a relatively frequent event (30%) in ovarian carcinomas and this observation is especially frequent for serous, transitional cell and anaplastic histological subtypes. Mucinous and endometrioid ovarian tumours showed only short interstitial deletions (4/11, 36%). The overall frequency of the short deletions was relatively low (7/43, 16%) in our panel of carcinomas. Amplification of c-erbB-2/neu oncogene was detected in 32% (11/34) of the carcinomas tested; the gene was amplified only in those histological subtypes in which high incidence of LOH on chromosome 17 was observed, and was associated with advanced stages of the disease. We conclude that different histological types of tumour may have different aetiological mechanisms, and tumour-suppressor genes on chromosome 17 might be associated specifically with serous and transitional cell ovarian carcinomas.
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PMID:Allele loss from large regions of chromosome 17 is common only in certain histological subtypes of ovarian carcinomas. 893 40

Thirty percent of human breast cancers have amplification of ERBB2, often in conjunction with mutations in p53. The most common p53 mutation in human breast cancers is an Arg-to-His mutation at codon 175, an allele that functions in a dominant oncogenic manner in tumorigenesis assays and is thus distinct from loss of p53. Transgenic mice expressing mouse mammary tumor virus-driven neu transgene (MMTV-neu) develop clonal mammary tumors with a latency of 234 days, suggesting that other events are necessary for tumor development. We have examined the role of mutations in p53 in tumor development in these mice. We have found that 37% of tumors arising in these mice have a missense mutations in p53. We have directly tested for cooperativity between neu and mutant p53 in mammary tumorigenesis by creating bitransgenic mice carrying MMTV-neu and 172Arg-to-His p53 mutant (p53-172H). In these bitransgenic mice, tumor latency is shortened to 154 days, indicating strong cooperativity. None of the nontransgenic mice or the p53-172H transgenic mice developed tumors within this time period. Tumors arising in the p53-172H/neu bitransgenic mice were anaplastic and aneuploid and exhibited increased apoptosis, in distinction to tumors arising in p53-null mice, in which apoptosis is diminished. Further experiments address potential mechanisms of cooperativity between the two transgenes. In these bitransgenic mice, we have recapitulated two common genetic lesions that occur in human breast cancer and have shown that p53 mutation is an important cooperating event in neu-mediated oncogenesis.
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PMID:neu/ERBB2 cooperates with p53-172H during mammary tumorigenesis in transgenic mice. 915 14

Chromosome 17 is one of the most frequently altered chromosomes in malignant breast cancer. At least four genes implicated in breast cancer reside on chromosome 17 (p53, 17p13; Her-2/neu/ERBB2, 17q12; BRCA1, 17q21; and nm23, 17q22). In addition, allelic imbalance has been described for at least five regions of chromosome 17. We have previously shown that the introduction of a normal human chromosome 17 into the breast cancer cell line MCF7 by microcell mediated chromosome transfer (MMCT) results in the in vitro growth arrest of these cells within 8 weeks, suggesting the presence of a growth suppressor on chromosome 17. Additionally, we have shown that the tumor suppressor gene p53 is not responsible for this phenotype, as it is wild type in MCF7 cells, and overexpression has no effect on either the in vitro or in vivo growth of these cells. We have further localized this growth suppressor gene to 17q24-q25 by transfer of chromosome 17 hybrids containing defined deletions. Whereas transfer of hybrids that contained an intact 17q (delta43/A9 and delta26/A9) resulted in growth arrest, two hybrids with overlapping deletions at 17q24-q25, had no effect on growth of MCF7 cells. Molecular analyses revealed that 50/70 (71%) of the resulting delta2/MCF7 or delta624/MCF7 MMCT clones retained an intact introduced chromosome 17. In contrast, only 8/34 (24%) of delta43/MCF7 revertants (deleted for 17p13.1-pter) which escaped growth arrest showed no breakage of the introduced chromosome 17. We did not observe a preferential loss of an intragenic BRCA1 marker in the MMCT hybrids, excluding BRCA1 as the gene responsible for this growth arrest phenotype. These data therefore implicate a new growth suppressor gene involved in breast cancer that is localized to chromosome 17q24-q25.
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PMID:Localization of a growth suppressor activity in MCF7 breast cancer cells to chromosome 17q24-q25. 917 10

The dysregulation of specific oncogenes due to either mutation or activation has previously been reported in a small number of patients with myeloma but the extent of oncogene dysregulation during the course of the disease is not known. The oncoprotein phenotype of plasma cells in 146 bone marrow samples from 81 patients with multiple myeloma was determined by dual colour flow cytometry using a predetermined panel of 8 monoclonal antibodies. High intensity CD38 expression was used to distinguish the plasma cell population and the cells were permeabilised to detect intracellular antigen expression. In situ hybridization using biotinylated cDNA probes for c-myc and bcl-2 was used to determine mRNA expression and to validate the flow cytometric assay. The normal range of expression for each of 6 oncoproteins (c-myc, c-fos, c-neu, bcl-2, p-ras, p53 mutant) and 2 tumour suppressor gene products (p53 wild and Rb) was determined in plasma cells from 33 normal bone marrows. Disease progression was associated with the concurrent abnormal expression of at least one oncogene and one tumour suppressor gene where as stable disease was associated with a normal expression of at least one or both (chi2 = 34.1; p < 0.001). At diagnosis there was a correlation between serum beta2 microglobulin and the concurrent overexpression of both an oncoprotein and a tumour suppressor gene product. Longitudinal studies of 33 different patients over 4 years, suggests that the progressive evolution of myeloma is a multistep process of genomic instability producing ongoing alterations in the expression of both oncogenes and tumour suppressor genes.
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PMID:Disease progression in patients with multiple myeloma is associated with a concurrent alteration in the expression of both oncogenes and tumour suppressor genes and can be monitored by the oncoprotein phenotype. 925 Aug 26

TP53 abnormalities have been reported as an early event in the process of cellular transformation of human breast cancers, and involved in mammary-tumor evolution, from in situ to invasive disease. In this study, node-negative (N-) tumors were examined for TP53 allelic loss in relation to different genetic instability events, including allelic loss at chromosome 17p13.3 and c-H-ras-1 loci, as well as alteration of the c-myc and c-erbB-2/neu oncogenes. TP53 allelic loss was analyzed to determine whether such an abnormality was the more important, among other genetic events, in the N- tumors, whether it appeared independently of these genetic events, and whether accumulation of genetic events arises in this group of breast tumors. Clinicopathological parameters were also examined. Loss of heterozygosity (LOH) at the TP53 gene appears the most frequent alteration detected (26% vs. 13%, 8%, 9% and 3% for LOH at D17S30 and c-H-ras-1 loci, and amplification of c-myc and c-erbB-2/neu respectively). There was no association between LOH at the TP53 locus and other genetic events. Among clinicopathological parameters, significant associations were observed only with estrogen-receptor-negative tumors (p = 0.05). Our results demonstrate that LOH at TP53 arises more frequently in the N- breast cancer, thus supporting earlier findings suggesting that TP53 abnormality has a role early in the pathogenesis of breast lesions. Moreover, the data indicate that accumulation of many genetic events occurs at a low level in N- breast tumors, and that TP53 abnormality occurs independently of these genetic events.
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PMID:Loss of heterozygosity at the TP53 gene: independent occurrence from genetic instability events in node-negative breast cancer. 925 97

Human solid tumors develop multiple genetic evolutionary abnormalities as they evolve. Studies that have focused primarily on early colorectal cancer have suggested that genetic instability is a prominent feature of preinvasive disease. At least two separate mechanisms for the generation of genetic instability have been identified. The first, which involves widespread microsatellite instability in near-diploid cells, affects less than one-fifth of colon cancers. The second form of genetic instability is characterized by the development of p53 gene abnormalities that result in gross aneuploidy and multiple structural chromosomal changes. p53/aneuploidy affects most colon cancers, breast cancers, and many other solid tumors. This genetic evolutionary change commonly occurs at the interface between severe dysplasia and invasive disease. Specific post-aneuploid sequences of genetic changes that are relevant to tumor progression often involve the accumulation of multiple gain-of-function abnormalities in individual cells. The co-occurrence of Her-2/neu overexpression and EGF receptor overexpression in the same aneuploid cells defines an adeno/squamous genetic evolutionary sequence that is common to ductal breast cancers, non-small cell lung cancers, and other solid tumors. Later steps in this sequence include ras and c-myc overexpression. The neuroendocrine genetic evolutionary sequence is a separate branch of the p53/aneuploidy sequence with distinctive features that include loss of Rb and raf1 overexpression. Her-2/neu overexpression is not characteristic of this sequence; c-myc amplification/overexpression is common to both p53-associated sequences. The neuroendocrine sequence is found in small cell carcinoma of the lung and in minor proportions of other solid tumors, including breast cancer. Multiparameter cell-based methods are especially well suited for elucidation in human solid tumors of the genetic evolutionary sequences that could provide a rational scientific basis for determining prognosis and for optimizing therapy in individual cancer patients.
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PMID:Common patterns of genetic evolution in human solid tumors. 929 7

Extensive research has led to accumulation of common hereditary evidence concerning ovarian and breast cancer, suggesting that these two cancers can be considered as one type. Subsequently, women with breast cancer are susceptible to the risk of developing ovarian cancer. Highly expressed oncogenes such as bcl-2, HER2/neu and others or mutated suppressor genes such as p53 or BRCA1 have been characterised as hereditary susceptibility genes leading to syndromes such as breast/ovarian cancer syndrome, Li-Fraumeni and others. Furthermore, these genetic alterations can cause potent chemoresistance by inhibiting induction of apoptosis after DNA damage caused by chemotherapy and/or radiotherapy. Presently, molecular onco-biology has enabled us not only to detect susceptibility to ovarian and breast cancer but also ways to inhibit their further progression or even circumventing chemoresistance mechanisms after their development by gene therapy using delivery vectors such as liposomes or viruses, by which we can replace wild-type tumour suppressor genes or by using antigene, antisense oligonucleotides and antisense RNA leading to reduced oncogene expression, enabling induction of apoptosis after DNA damage into chemoresistant tumour cells. Furthermore efflux-genes such as MDR-1 or MRP can be circumvented, suicide-genes can be employed which can facilitate sensitivity by encoding enzymes capable of converting inactive forms of a drug into toxic antimetabolites and immunotherapy can be achieved, by transfection of tumour cells with adenoviral vectors encoding immunomodulators such as IL-2 or MHC molecules. Thus, molecular biology appears to be a very strong element for the screening, diagnosis, therapy and prognosis of ovarian and breast cancer. However, consistent future research is greatly needed because many points concerning ovarian and breast cancer genetics are still unknown. Finally, we strongly believe that gene therapy could be extremely useful when is combined with conventional therapy against ovarian and breast tumours.
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PMID:Molecular aspects of breast and ovarian cancer. 937 59

We assessed distributions of breast cancer prognostic biomarkers by race/ethnicity and socioeconomic position among paraffin-embedded tumor biopsy specimens from 135 US women (48 white women, 44 black women, 43 Asian women) diagnosed with breast cancer between 1966 and 1990. No racial/ethnic or socioeconomic differences in distributions were observed for tumor stage, lymph node involvement, estrogen, progesterone, and epidermal growth factor receptors, oncogenes such as Her2/neu and p53, cytoplasmic proteins cathepsin-D and ps2, and two indices of cell growth, Ki67 and DNA ploidy, adjusting for age at diagnosis, menopausal status, place of birth and, for racial/ethnic comparisons, working class composition of census block-group at diagnosis. Black and Asian women, however, were 3.5 times (95% confidence interval [CI] = 1.2, 10.1) and 3.7 times (95% CI = 1.3, 10.6), respectively more likely than white women to have a tumor size of > or = 20 mm, and Asian women were 3.4 times (95% CI = 1.1, 10.4) more likely than black women to be positive for androgen receptor, adjusting for these same factors. No differences in distributions by socioeconomic position were observed for these latter two tumor characteristics. These data suggest that racial/ethnic and socioeconomic disparities in breast cancer survival are unlikely to be explained solely by differential distributions of molecular breast cancer prognostic biomarkers.
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PMID:Race/ethnicity, social class, and prevalence of breast cancer prognostic biomarkers: a study of white, black, and Asian women in the San Francisco bay area. 938 54

The expression of hormone receptors (estrogen and progesterone), c-erb-B2 (neu), p53, and Ki-67) was studied by immunohistochemical analysis in a series of 94 carcinomas in situ of the breast. The tumors were classified in two (high grade vs. low grade) and three (high grade vs. intermediate grade vs. low grade) categories. High-grade carcinomas were well defined by biologic markers showing statistically significant differences for all of the parameters tested. No clear biologic distinction, however, between low-grade and intermediate-grade cancers could be obtained. Negative progesterone receptors and a high proliferative index are the best discriminant parameters for the final assignment of doubtful cases.
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PMID:Ductal carcinoma in situ of the breast: correlation between histologic classifications and biologic markers. 938 58

Recent experimental evidence obtained in Scid mice has suggested that the metastatic process is in large part epigenetically regulated and undergoes partial reversion once the metastatic process is completed: the metastatic colonies become more engaged in the process of growing in situ than actively metastasizing. Based on this experimental evidence, examples were sought of metastatic human cancers where similar reversion to an in situ growth state was occurring. Review of 200 cases of metastatic human breast cancer revealed a 21 per cent incidence of reversion to a ductal carcinoma in situ (DCIS) growth pattern within axillary nodal metastases. The revertant DCIS areas were characterized by an intact and circumferential basement membrane, as demonstrated by extracellular laminin and type IV collagen immunoreactivity. These revertant DCIS areas could be distinguished from primary DCIS, however, by the absence of surrounding myoepithelial cells in the former, identified in the latter by their positive maspin, S-100, and smooth muscle actin immunoreactivity. The pattern of revertant DCIS, poorly differentiated (comedo) (13 per cent), intermediate (non-comedo) (6 per cent), or well-differentiated (non-comedo) (2%), exhibited complete 100 per cent concordance with the primary DCIS pattern. The concordance of histological patterns held true for even the subtypes of DCIS determined by architectural pattern, such as the micropapillary or cribriform subtypes. Nuclear size by digital image analysis and Her-2/neu, p53, and Ki-67 status in the revertant DCIS also exhibited complete concordance with the primary DCIS counterparts. Cases exhibiting a revertant DCIS pattern tended to be ER-negative/EGFR-positive and exhibited significant nodal involvement (mean number, 9; mean area, 90 per cent) compared with cases lacking a revertant pattern (mean number, 4; mean area, 15 per cent) (P < 0.01) These findings suggest that reversion of the metastatic phenotype may also be occurring within autochthonous human metastasis.
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PMID:'Revertant' DCIS in human axillary breast carcinoma metastases. 939 32


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