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)

Medullary breast cancer (MBC) is a rare, diagnostically difficult, pathological subtype. Despite being high grade, it has a good prognosis. MBC patients have an excess of BRCA1 germ-line mutation and reliable identification of MBC could help to identify patients at risk of carrying germline BRCA1 mutations or in whom chemotherapy could be avoided. The aim of this study was therefore to improve diagnosis by establishing an MBC protein expression profile using immunohistochemistry (IHC) on tissue-microarrays (TMA). Using a series of 779 breast carcinomas ('EC' set), diagnosed initially as MBC, a double-reading session was carried out by several pathologists on all of the histological material to establish the diagnosis as firmly as possible using a 'medullary score'. Only MBCs with high scores, i.e. typical MBC (TMBC) (n=44) and non-TMBC grade III with no or low scores (n=160), were included in the IHC study. To validate the results obtained on this first set, a control series of TMBC (n=17) and non-MBC grade III cases (n=140) ('IPC' set) was studied. The expression of 18 proteins was studied in the 61 TMBCs and 300 grade III cases from the two sets. The global intra-observer concordance of the first reading for the diagnosis of TMBC was 94%, with almost perfect kappa (kappa) of 0.815. TMBC was characterized by a high degree of basal/myoepithelial differentiation. In multivariate analysis with logistic regression, TMBC was defined by the association of P-cadherin (R=2.29), MIB1 > 50 (R=3.80), ERBB2 negativity (R=2.24) and p53 positivity (RR=1.45).
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PMID:Typical medullary breast carcinomas have a basal/myoepithelial phenotype. 1616 61

The serine-threonine protein phosphatase PPM1D is likely to play an important role in tumorigenesis. Through inactivation of p38 MAPK, PPM1D acts as a negative feedback regulator of p53 tumour suppressor gene and controls the expression of other cell cycle regulatory proteins, such as CCND1. In addition, recent knock-out mouse studies implicated PPM1D in the regulation of p16 expression and the RB tumour suppressor pathway. Here we explored the role of PPM1D aberrations in primary breast cancer. PPM1D copy number analysis showed amplification in 11% (13/117) of the tumours and quantitative real-time RT-PCR revealed a significant correlation (p = 0.0148) between PPM1D amplification and increased expression. PPM1D amplification occurred almost exclusively in tumours with wild-type p53 suggesting that these events are mutually exclusive and further confirming the role of PPM1D as a negative regulator of p53. Interestingly, PPM1D amplification was associated with ERBB2 expression (p = 0.0001) thus implying that PPM1D aberrations occurs in tumours with poor prognosis. We also explored the expression levels of two possible downstream targets of PPM1D. However, immunohistochemical analyses revealed no differences in the staining patterns of CCND1 and p16 proteins in tumours with or without PPM1D aberrations, thus suggesting that previous data from animal model experiments is not directly transferable to primary human tumours. On the other hand, these key cellular proteins are likely to be regulated through a complex fashion in breast cancer and apparently PPM1D represents only one of these mechanisms. Taken together, our findings substantiate an important role for PPM1D in breast cancer.
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PMID:The serine-threonine protein phosphatase PPM1D is frequently activated through amplification in aggressive primary breast tumours. 1625 85

Specific abnormalities in cancers are the best molecular targets of therapeutics, which is exemplified by trastuzumab. ERBB2 amplification is present in 15-30% of invasive ductal carcinomas, and its overexpression was associated with poor prognosis. c-MYC amplification is present in 13-19%, but other forms of oncogene activation are rare. Germline mutations of BRCA1 and BRCA2 are responsible for familial breast cancers. Their somatic mutations in sporadic breast cancers are rare, but chromosomal losses are frequent. Inactivation of BRCA1 by its promoter methylation is also frequent. p53 mutations are present in 20-25% of sporadic breast cancers, and inactivation of its pathway is present in most of them. Further molecular analysis will reveal new targets for diagnosis and therapeutics.
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PMID:[Genes involved in breast cancers]. 1652 32

EGFR and erbB-2 are targets for specific cancer therapy. The purpose of this study was to examine the frequency and clinicopathological correlations of gene amplification, protein expression, and mutations of EGFR and ERBB2 in serous carcinoma, the most common and aggressive type of ovarian cancer. Tissue microarray constructed of 398 carcinomas was examined by chromogenic in situ hybridization (CISH) and by immunohistochemistry. Cases with amplification of EGFR by CISH were further analyzed by fluorescence in situ hybridization. One hundred ninety-eight samples were analyzed for mutations in exons 18, 19, or 21 of EGFR and in exon 20 of ERBB2 using denaturating high-performance liquid chromatography and direct sequencing. Amplification of EGFR was present in 12% (41/333), low-level gain in 43% (144/333), and protein overexpression in 17% (66/379) of the tumors. Both increased copy number and overexpression of EGFR were associated with high tumor grade, greater patient age, large residual tumor size, high proliferation index, aberrant p53, and poor patient outcome. Furthermore, increased copy number of EGFR was associated with increased copy number of ERBB2. No mutations were identified in EGFR, whereas one tumor had an insertion mutation in exon 20 of ERBB2. Both amplification and protein overexpression of EGFR occur in serous ovarian carcinoma, but EGFR copy number has a stronger prognostic value. This makes EGFR amplification a potentially useful criterion for selecting patients in clinical trials testing the effect of EGFR inhibitors in serous ovarian carcinoma.
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PMID:Gene amplification, mutation, and protein expression of EGFR and mutations of ERBB2 in serous ovarian carcinoma. 1660 61

Methionine deprivation stress (MDS) eliminates mitotic activity in melanoma cells regardless of stage, grade, or TP53 status, whereas it has a negligible effect on normal skin fibroblasts. In most cases, apoptosis accounts for the elimination of up to 90% of tumor cells from the culture within 72 hours after MDS, leaving a scattered population of multinucleated resistant cells. Loss of mitosis in tumor cells is associated with marked reduction of cyclin-dependent kinase (CDK) 1 transcription and/or loss of its active form (CDK1-P-Thr(161)), which is coincident with up-regulation of CDKN1A, CDKN1B, and CDKN1C (p21, p27, and p57). Expression of the proapoptotic LITAF, IFNGR, EREG, TNFSF/TNFRSF10 and TNFRSF12, FAS, and RNASEL is primarily up-regulated/induced in cells destined to undergo apoptosis. Loss of Aurora kinase B and BIRC5, which are required for histone H3 phosphorylation, is associated with the accumulation of surviving multinucleated cells. Nevertheless, noncycling survivors of MDS are sensitized to temozolomide, carmustin, and cisplatin to a much greater extent than normal skin fibroblasts possibly because of the suppression of MGMT/TOP1/POLB, MGMT/RAD52/RAD54, and cMET/RADD52, respectively. Sensitivity to these and additional genotoxic agents and radiation may also be acquired due to loss of cMET/OGG1, reduced glutathione reductase levels, and a G(2)-phase block that is a crucial step in the damage response associated with enhancement of drug toxicity. Although the genes controlling mitotic arrest and/or apoptosis in response to low extracellular methionine levels are unknown, it is likely that such control is exerted via the induction/up-regulation of tumor suppressors/growth inhibitor genes, such as TGFB, PTEN, GAS1, EGR3, BTG3, MDA7, and the proteoglycans (LUM, BGN, and DCN), as well as the down-regulation/loss of function of prosurvival genes, such as NFkappaB, MYC, and ERBB2. Although MDS targets several common genes in tumors, mutational variability among melanomas may decide which metabolic and signal transduction pathways will be activated or shutdown.
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PMID:Mitotic arrest, apoptosis, and sensitization to chemotherapy of melanomas by methionine deprivation stress. 1690 95

In lung cancer, an association was made between drastic clinical response to epidermal growth factor receptor (EGFR) inhibitors and the presence of somatic mutations within the tyrosine kinase domain of the EGFR. In some cases, patients with partial response or disease stabilization do not always have EGFR-mutated tumors. To go further in the characterization of the EGF pathway, we screened EGFR, ERBB2, ERBB3, KRAS, BRAF, and PIK3CA for mutations in 2 groups of White patients with nonsmall cell lung cancer (45 cancers from women and 46 cancers from men). Associations between TP53 mutations, clinicopathologic parameters, and EGF pathway molecular alterations were analyzed. All mutations were exclusive and essentially found in EGFR and KRAS. We demonstrated that EGFR mutations were linked to female sex, absence of smoking, late age at diagnosis, and adenocarcinoma (ADC) with bronchioloalveolar (BAC) features. Moreover, in invasive ADC with BAC component, microdissection assays showed that mutations were retrieved in both tumor subtypes suggesting that EGFR mutations appear early in lung carcinogenesis. On the contrary, KRAS mutations correlated with smoking, younger age at diagnosis, and ADC subtype regardless of BAC differentiation. These results suggest the existence of distinct carcinogenesis pathways both leading to disruption of EGF regulation and targeted either by tobacco carcinogens or by unidentified toxic. The identification of BAC features in ADC helps clustering patients that are more likely to fit the EGFR-mutated group.
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PMID:Epidermal growth factor receptor mutation in lung cancer are linked to bronchioloalveolar differentiation. 1700 Nov 63

Alterations of TP53 and ERBB2 have been shown to play important roles in the prognosis of breast cancer. The primary objective of this study is to characterize TP53 mutation types in node negative breast cancer and investigate their prognostic value, alone and in combination with ERBB2 amplification status. TP53 mutational status (exons 2-10) and ERBB2 amplification status were determined in tumor specimens from a prospective cohort of 543 women with node-negative breast cancer. During a median follow-up of 120 months, there were 111 disease recurrences, and 81 disease-related deaths (3 with cancer; 78 from cancer). Of 543 women, 133 (24.5%) carried mutations in exons 4-9 of the TP53 gene. Seventy-one (53.4%) of these mutations were missense; whereas 62 (46.6%) were protein-truncating mutations. Women whose tumors had missense TP53 mutations were found to be at significantly higher risk of recurrence and death compared to those with wild type TP53, and they also tended to have worse prognosis compared to those with truncating mutations. Those with short truncated proteins tended to have good prognosis compared to those with long truncated proteins, but the risk of recurrence and death did not differ between those whose tumors exhibited conserved versus non-conserved mutations. Missense mutations, in combination with ERBB2 amplification, were observed in 4.6% of the tumors and dramatically affected the disease-specific survival (DSS) and disease-free survival (DFS) of the breast cancer patients. Our study suggests that the type of TP53 mutation, especially missense mutation, is a strong prognostic indicator for DFS and DSS in node-negative breast cancer, particularly in combination with ERBB2 amplification.
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PMID:Type of TP53 mutation and ERBB2 amplification affects survival in node-negative breast cancer. 1722 Nov 57

Women carrying germ-line mutations in BRCA1 are strongly predisposed to developing breast cancers with characteristic features also observed in sporadic basal-like breast cancers. They appear as high-grade tumors with high proliferation rates and pushing borders. On the molecular level, they are negative for hormone receptors and ERBB2, display frequent TP53 mutations, and express basal epithelial markers. To study the role of BRCA1 and P53 loss of function in breast cancer development, we generated conditional mouse models with tissue-specific mutation of Brca1 and/or p53 in basal epithelial cells. Somatic loss of both BRCA1 and p53 resulted in the rapid and efficient formation of highly proliferative, poorly differentiated, estrogen receptor-negative mammary carcinomas with pushing borders and increased expression of basal epithelial markers, reminiscent of human basal-like breast cancer. BRCA1- and p53-deficient mouse mammary tumors exhibit dramatic genomic instability, and their molecular signatures resemble those of human BRCA1-mutated breast cancers. Thus, these tumors display important hallmarks of hereditary breast cancers in BRCA1-mutation carriers.
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PMID:Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. 1762 82

The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast cancer. ATM signalling is constitutively activated in early stages of diverse types of human malignancies and cell culture models in response to oncogene-induced DNA damage providing a barrier against tumour progression. As BRCA1 and BRCA2 are also components of the genome maintenance network and their mutations predispose to breast cancer, we have examined the ATM expression in human breast carcinomas of BRCA1/2 mutation carriers, sporadic cases and familial non-BRCA1/2 patients. Our results show that ATM protein expression is aberrantly reduced more frequently among BRCA1 (33%; P=0.0003) and BRCA2 (30%; P=0.0009) tumours than in non-BRCA1/2 tumours (10.7%). Furthermore, the non-BRCA1/2 tumours with reduced ATM expression were more often estrogen receptor (ER) negative (P=0.0002), progesterone receptor (PR) negative (P=0.004) and were of higher grade (P=0.0004). In our series of 1013 non-BRCA1/2 cases, ATM was more commonly deficient (20%; P=0.0006) and p53 was overabundant (47%; P<0.0000000001) among the difficult-to-treat ER/PR/ERBB2-triple-negative subset of tumours compared with cases that expressed at least one of these receptors (10 and 16% of aberrant ATM and p53, respectively). We propose a model of 'conditional haploinsufficiency' for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM in tumours of BRCA1/2 mutation carriers, with implications for genomic instability and curability of diverse subsets of human breast cancer.
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PMID:The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer. 1798 90

We describe the newly established cell line CS-99 derived from a uterine carcinosarcoma retaining features of the sarcomatous phenotype in vitro. CS-99 cells exhibit a mesenchymal morphology with predominantly spindle-shaped cells at nonconfluence turning to pleomorphic appearance at confluence. The mesenchymal phenotype was evidenced immunohistochemically by strong vimentin and moderate SM-actin, which was similar to the sarcomatous component of the primary tumor. P53 was overexpressed in a subset of CS-99 cells. Epithelial membrane antigen was moderately expressed whereas other markers including pan CK, CK 5/6, CK 34, epidermal growth factor receptor, desmin, carcinoembryonic antigen, S100, KIT, ERBB2, and the hormone receptors, estrogen receptor and progesterone receptor revealed either weak or no specific staining in CS-99 cells. High self-renewal capacity corresponded to the population doubling time of 23 h in high passage. CS-99 cells were able to develop three-dimensional tumor spheroids in vitro. Cytogenetic analysis and multicolor fluorescence in situ hybridization of CS-99 demonstrated an almost stable karyotype including numerical changes +8, +18, and +20 and translocations, amongst others der(1)t(1;2), der(1)t(1;7), der(2)t(2;19), der(5)t(5;8), and der(5)t(5;14). Taken together, the cell line CS-99 exhibits strong growths dynamics and a complex but stable karyotype in higher passages, and can be further a useful in vitro model system for studying tumor biology of carcinosarcomas.
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PMID:Characterization of a newly established uterine carcinosarcoma cell line featuring the sarcomatous phenotype of the tumor in vitro. 1833 12


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