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)

Malignant transformation is the result of genetic events, translated into sequential acquisitions of multiple abnormalities in the control of cellular growth and cell cycle regulation. We determined the expression of the estrogen receptor (ER), progesterone receptor (PR), c-erbB-2 and p53 gene products in a patient with mixed (ductal and lobular) invasive breast carcinoma bearing different coexisting lesions. The purpose of the study was to establish a possible correlation between the expression pattern for these molecules and the histological appearance of the breast tumor. Our results showed no positivity for ER. PR expression was restricted to normal epithelium, simple hyperplasia and in situ carcinoma. c-erbB-2 was detected in all lesions with the exception of normal epithelium and immunostaining for p53 was found positive only in in situ and invasive carcinoma. These findings support the hypothesis of tumorigenesis as a multistep process and as a sum of changes, each representing an advantageous acquisition for the malignant cells' behavior. The loss of hormone receptors' expression occurred as an early event in this case, while the p53 mutations were found only in more advanced neoplastic lesions.
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PMID:Sequential phenotype changes in progressive lesions of breast carcinoma. 1747 65

Presented herein is an unusual case of intraductal tubular carcinoma, intestinal type, of the pancreas. This tumor was characterized by intraductal adenoma with a few malignant foci, and also by entire involvement of the main pancreatic duct and no involvement of its branches. A 67-year-old man was admitted to hospital because of abdominal pain. On endoscopy and endoscopic retrograde cholangiopancreatography, irregular pancreatic duct was seen. No mucus secretion was observed on endoscopy. Because a biopsy showed tubular atypical cells, pancreato-duodenectomy was performed. Grossly, the entire main pancreatic duct had intraductal tumor, sparing its branches. No intraductal mucus was noted. Microscopically, the entire main pancreatic duct had proliferation of tubular adenomatous tumor without secretory mucins. Goblet cells were present in some areas. No pyloric type tubules were recognized. Malignant transformation was present in a few areas. No invasive features were recognized. On mucin histochemistry the tumor cell cytoplasm contained a little or no neutral and acidic mucus, and no secretory mucins were recognized. Immunohistochemically, the tumor cells were positive for cytokeratins (CK), CK 8, 9, 18, 19 and 20, epithelial membrane antigen, CDX2, carbohydrate antigen 19-9, and Ki-67 (labeling 30%), MUC2, MUC5AC and MUC6, and CD10. The tumor cells were negative for C-erbB2, MUC1, trypsin, pancreatic amylase and pancreatic lipase. The tumor cells were negative for p53 protein, but the malignant foci were positive for p53 protein and had high Ki-67 antigen (labeling 60%). The patient was free of disease 4 years after the operation. In summary, presented here is an extremely rare case of intraductal tubular carcinoma, intestinal type, showing focal malignant foci.
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PMID:Intraductal tubular carcinoma, intestinal type, of the pancreas. 1912 Oct 93

Cutaneous melanoma is one of the leading causes of cancer-related death. Malignant transformation of epidermal melanocytes is a multifactorial process involving cell cycle and death control pathways. The purpose of this study was to analyze the immunohistochemical expression of cell-cycle-related and apoptosis-related proteins in cutaneous superficial spreading melanomas using the tissue microarray technique to further understand tumor development. A total of 20 samples of in-situ melanomas and 44 melanomas <or=1.0 mm were analyzed in conventional sections whereas 72 melanomas greater than 1.0 mm and 29 metastases were evaluated by tissue microarray. The sections were stained for the following proteins: p16INK4 (p16), cyclin D1, cyclin-dependent kinase 4 (Cdk4), retinoblastoma protein, tumor suppressor protein p53, and p21 cell cycle regulator (p21) using a streptavidine-biotin-peroxidase technique for immunohistochemistry. Thick melanomas (>1.0 mm) and metastases lost p16 expression in 100% of the cases and in-situ and thin melanomas (<or=1.0 mm) had low rate of p16 expression (7.9%). When comparing thin versus thick melanomas, thin melanomas showed higher expression of cyclin D1 and cytoplasmatic Cdk4, and thick melanomas had increased expression of nuclear Cdk4, tumor suppressor protein p53, and p21. Primary tumors, when compared with metastases, had higher cytoplasmatic Cdk4 expression. None of the studied proteins influenced overall or disease-free survival. Our results suggest that loss of p16 expression was a constant feature in primary and metastatic melanomas. Cyclin D1 expression seems to be related to initial phases of melanoma development. An increase in p21 expression could represent a cell cycle control in proliferating cells with reduced p16 and/or increased nuclear Cdk4 expression.
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PMID:Proteins involved in pRb and p53 pathways are differentially expressed in thin and thick superficial spreading melanomas. 1936 1

Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (for example, oxidative, replicative, metabolic and proteotoxic stress, and DNA damage). Adaptation to this stress phenotype is required for cancer cells to survive, and consequently cancer cells may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Thus, targeting these non-oncogene dependencies in the context of a transformed genotype may result in a synthetic lethal interaction and the selective death of cancer cells. Here we used a cell-based small-molecule screening and quantitative proteomics approach that resulted in the unbiased identification of a small molecule that selectively kills cancer cells but not normal cells. Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, but it has little effect on either rapidly or slowly dividing primary normal cells. Significant antitumour effects are observed in piperlongumine-treated mouse xenograft tumour models, with no apparent toxicity in normal mice. Moreover, piperlongumine potently inhibits the growth of spontaneously formed malignant breast tumours and their associated metastases in mice. Our results demonstrate the ability of a small molecule to induce apoptosis selectively in cells that have a cancer genotype, by targeting a non-oncogene co-dependency acquired through the expression of the cancer genotype in response to transformation-induced oxidative stress.
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PMID:Selective killing of cancer cells by a small molecule targeting the stress response to ROS. 3004 3

Schneiderian papilloma (SP) is classified into three types: inverted, oncocytic, and exophytic. Malignant transformation occurs in 10% of SP; most are inverted and oncocytic types. Malignant transformation of polypoid exophytic SP is exceptional; only two cases have been reported in the English literature. A 58-year-old man consulted our hospital because of nasal obstruction. Nasal endoscopy and imaging modalities showed a polyp in the right nasal cavity. Biopsy findings showed compatibility with SP. However, since fludeoxyglucose positron emission tomography (FDG-PET) showed signals, polypectomy was performed. Grossly, the polyp was reddish white and measured 2 cm. Histologically, the polyp consisted of a non-invasive squamous cell carcinoma (SCC) component (70%), a mature squamous component (20%), and Schneiderian epithelium (10%). Vague koilocytosis was present in the SCC component. The three components were arranged in an exophytic papillary pattern. Immunohistochemically, the non-invasive SCC component was positive for cytokeratins (AE1/3, CAM5.2, CK5/6), p63, p53, and Ki67 (labeling 50%). The mature squamous component was positive for cytokeratins (AE1/3, CAM5.2 and CK5/6), p63, and Ki67 (labeling 6%). The Schneiderian component was positive for cytokeratins (AE1/3, CAM5.2, and CK5/6), p63, and Ki-67 (labeling 4%). The tumor was HPV negative in the three components. The polyp was diagnosed as exophytic Schneiderian carcinoma arising from exophytic SP. The patient is now free from tumor 4 years after the operation.
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PMID:Malignant transformation of exophytic Schneiderian papilloma of the nasal cavity. 2236 May 8

Changes in histological and genetic characteristics were investigated in 18 paired primary and recurrent oligodendroglial tumors, using sequencing analysis for isocitrate dehydrogenase (IDH) 1 and 2 gene mutation, Ki-67 and p53 immunohistochemistry, and fluorescent in situ hybridization for loss of heterozygosity of chromosomes 1p and 19q (1p/19q co-deletion). Malignant transformation occurred in 5 of 8 cases with World Health Organization (WHO) grade II tumors, but in 0 of 10 cases with WHO grade III tumors progressing to glioblastoma. Thirteen of the 18 cases carried IDH1 gene mutation. Tumors with IDH1 mutation tended to survive for longer, even after recurrence, but newly developed microvascular proliferation, tumor necrosis, and elevated Ki-67 labeling index were common. Eleven of the 13 IDH1-mutation tumors had either 1p/19q co-deletion or nuclear expression of p53, but all 5 IDH1/2 wild-type tumors had neither. All cases had the same profile for 1p/19q status at recurrence, but nuclear expression of p53 changed from negative to positive in 2 of 6 cases with IDH1 mutation and 1p/19q co-deletion. WHO grade II oligodendroglial tumors show a high rate of malignant transformation, possibly involving p53 in tumors with IDH1 mutation and 1p/19q co-deletion. Tumors with IDH1 mutation had a more aggressive histological phenotype despite their better prognosis.
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PMID:Clinical and histological characteristics of recurrent oligodendroglial tumors: comparison between primary and recurrent tumors in 18 cases. 2305 95

Histone methylation regulates normal stem cell fate decisions through a coordinated interplay between histone methyltransferases and demethylases at lineage specific genes. Malignant transformation is associated with aberrant accumulation of repressive histone modifications, such as polycomb mediated histone 3 lysine 27 (H3K27me3) resulting in a histone methylation mediated block to differentiation. The relevance, however, of histone demethylases in cancer remains less clear. We report that JMJD3, a H3K27me3 demethylase, is induced during differentiation of glioblastoma stem cells (GSCs), where it promotes a differentiation-like phenotype via chromatin dependent (INK4A/ARF locus activation) and chromatin independent (nuclear p53 protein stabilization) mechanisms. Our findings indicate that deregulation of JMJD3 may contribute to gliomagenesis via inhibition of the p53 pathway resulting in a block to terminal differentiation.
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PMID:Histone demethylase Jumonji D3 (JMJD3) as a tumor suppressor by regulating p53 protein nuclear stabilization. 2323 96

Juvenile-onset recurrent respiratory papillomatosis (RRP) is associated with low risk human papillomavirus (HPV) types 6 and 11. Malignant transformation has been reported solely for HPV11-associated RRP in 2-4% of all RRP-cases, but not for HPV6. The molecular mechanisms in the carcinogenesis of low risk HPV-associated cancers are to date unknown. We report of a female patient, who presented with a laryngeal carcinoma at the age of 24 years. She had a history of juvenile-onset RRP with an onset at the age of three and subsequently several hundred surgical interventions due to multiple recurrences of RRP. Polymerase chain reaction (PCR) or bead-based hybridization followed by direct sequencing identified HPV6 in tissue sections of previous papilloma and the carcinoma. P16(INK4A), p53 and pRb immunostainings were negative in all lesions. HPV6 specific fluorescence in situ hybridization (FISH) revealed nuclear staining suggesting episomal virus in the papilloma and a single integration site in the carcinoma. Integration-specific amplification of papillomavirus oncogene transcripts PCR (APOT-PCR) showed integration in the aldo-keto reductase 1C3 gene (AKR1C3) on chromosome 10p15.1. ArrayCGH detected loss of the other gene copy as part of a deletion at 10p14-p15.2. Western blot analysis and immunohistochemistry of the protein AKR1C3 showed a marked reduction of its expression in the carcinoma. In conclusion, we identified a novel molecular mechanism underlying a first case of HPV6-associated laryngeal carcinoma in juvenile-onset RRP, i.e. that HPV6 integration in the AKR1C3 gene resulted in loss of its expression. Alterations of AKR1C gene expression have previously been implicated in the tumorigenesis of other (HPV-related) malignancies.
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PMID:Integration of HPV6 and downregulation of AKR1C3 expression mark malignant transformation in a patient with juvenile-onset laryngeal papillomatosis. 2343 42

The aim of this review article was to evaluate the relationship and the possible etiological mechanisms between endometriosis, leiomyoma (LM) and adenomyosis and gynecological cancers, such as ovarian and endometrial cancer and leiomyosarcoma (LMS). MEDLINE was searched for all articles written in the English literature from July 1966 to May 2013. Reports were collected systematically and all the references were also reviewed. Malignant transformation of gynecologic benign diseases such as endometriosis, adenomyosis and LM to ovarian and endometrial cancer remains unclear. Hormonal factors, inflammation, familial predisposition, genetic alterations, growth factors, diet, altered immune system, environmental factors and oxidative stress may be causative factors in carcinogenesis. Early menarche, low parity, late menopause and infertility have also been implicated in the pathogenesis of these cancers. Ovarian cancers and endometriosis have been shown to have common genetic alterations such as loss of heterozygosity (LOH), PTEN, p53, ARID1A mutations. MicroRNAs have also been implicated in malignant transformation. Inflammation releases proinflammatory cytokines, and activates tumor associated macrophages (TAMS) and nuclear factor kappa b (NF-KB) signaling pathways that promote genetic mutations and carcinogenesis. MED12 mutations in LM and smooth muscle tumors of undetermined malignant potential (STUMP) may contribute to malignant transformation to LMS. A hyperestrogenic state may be shared in common with pathogenesis of adenomyosis, LM and endometrial cancer. However, the effect of these benign gynecologic diseases on endometrial cancer should be studied in detail. This review study indicates that endometriosis, LM, adenomyosis may be associated with increased risk of gynecological cancers such as endometrial and ovarian cancers. The patients who have these gynecological benign diseases should be counseled about the future risks of developing cancer. Further studies are needed to investigate the relationship between STUMPs, LMS and LM and characteristics and outcome endometrial carcinoma in adenomyotic patients.
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PMID:Endometriosis, leiomyoma and adenomyosis: the risk of gynecologic malignancy. 2428 48

Malignant transformation of the endothelium is rare, and hemangiosarcomas comprise only 1% of all sarcomas. For this reason and due to the lack of appropriate mouse models, the genetic mechanisms of malignant endothelial transformation are poorly understood. Here, we describe a hemangiosarcoma mouse model generated by deleting p53 specifically in the endothelial and hematopoietic lineages. This strategy led to a high incidence of hemangiosarcoma, with an average latency of 25 weeks. To study the in vivo roles of autocrine or endothelial cell autonomous VEGF signaling in the initiation and/or progression of hemangiosarcomas, we genetically deleted autocrine endothelial sources of VEGF in this mouse model. We found that loss of even a single conditional VEGF allele results in substantial rescue from endothelial cell transformation. These findings highlight the important role of threshold levels of autocrine VEGF signaling in endothelial malignancies and suggest a new approach for hemangiosarcoma treatment using targeted autocrine VEGF inhibition.
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PMID:Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice. 2462 76


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