UNIPROT:P04637 - FACTA Search

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

GENERAL DATA: There is now considerable evidence that high risk human papillomaviruses (HPV), such as HPV 16, are closely associated with cancer of the cervix. HPVs that are primarily transmitted through sexual contact, are found in over 99% of the cases of invasive cervical cancer. Although most women can be infected during their sexual life, a small minority is at risk for developing cancer. The long latency period between primary infection and cancer emergence suggests that additional factors are involved in the process of tumor development: sexual behavior, immune status, genetic predispositions, nutritional status, tobacco use, socio-economical level. NATURAL HISTORY: HPVs infect epithelial cells of the transformation zone of the cervix. As with other sexually transmitted diseases, the incidence of HPV infection is highest among young women. However, this viral infection is more often than not transient, because most individuals develop an effective type-specific immune response. Approximately 1% of the population has genital warts and 4% of women have cervical precancerous lesions: low grade squamous intraepithelial lesion (LGSIL) or high grade SIL. These last lesions preferentially observed in women aged 35-40 yrs are at high risk of progression towards an invasive cancer. ONCOGENIC POTENTIAL OF HPV: Pre-malignant and malignant cells arise as a result of HPV DNA integration in the host cellular genome, and overexpression of the viral E6 and E7 oncogenes. Cells acquire a proliferative advantage by escaping growth control exerted by p53 and p 105Rb. Both cellular proteins are indeed inactivated respectively by E6 and E7 proteins. Aneuploidy and karyotypic abnormalities are also key events in the tumor progression. A PREVENTABLE DISEASE: Cervical cancer is more than ever a preventable disease. While waiting for clinically applicable vaccination programs, strategies to prevent cervical cancer include 1) improved screening covering the widest possible population and using HPV testing, 2) close management and follow-up of women with precancerous lesions.
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PMID:[Epidemiology of cervical papillomavirus infections. Recent knowledge]. 1143 94

There is increasing evidence that there are different progression routes leading to invasive breast cancer, depending on histology and differentiation grade. The aim of this study was to determine alterations in the expression of proteins involved in proliferation and apoptosis in non-invasive and invasive ductal breast lesions. Immunohistochemistry was performed on 106 usual ductal hyperplasias (UDH), 61 DCIS lesions and 53 invasive ductal breast carcinomas. Increased proliferation (Ki67), overexpression of cyclin D1, HER-2/neu, p21 and p53, and decreased expression of bcl-2 and p27 could already be found in UDH. Significant differences between UDH and DCIS lesions were found for only one protein when UDH was compared with well-differentiated DCIS (p27), for three proteins when compared with intermediately differentiated DCIS (p21, cyclin D1, Ki-67), and for all proteins when compared with poorly-differentiated DCIS. Comparing DCIS with invasive lesions of same differentiation grade, proliferation was elevated in the invasive lesions. Altered expression of the other proteins was in general only slightly increased in the invasive lesion compared with DCIS. The number of proteins with altered expression per lesion was highest in poorly-differentiated lesions and was comparable between DCIS and invasive cancer of the same differentiation grade. In conclusion, the biggest changes in expression of these proliferation and apoptosis related proteins appear to occur during the transition from hyperplasia to DCIS; they probably play a minor role in the transition from DCIS to invasive breast lesion of same differentiation grade. Well-differentiated in situ and invasive breast lesions share many of the aberrations in expression of these proteins, as do poorly-differentiated in situ and invasive lesions. However, there are many differences between the well and poorly-differentiated lesions. This further supports the existence of different progression routes leading to breast cancer.
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PMID:Similarity in expression of cell cycle proteins between in situ and invasive ductal breast lesions of same differentiation grade. 1143 65

Genetic alterations at critical chromosome loci have been shown to be predictors of the progression of oral premalignancy-to-invasive cancer. We obtained a unique group of oral biopsies, initially collected during a prospective study designed to test the ability of OraTest (toluidine blue), to identify recurrent oral neoplastic lesions in patients with definite therapy for head and neck or upper aerodigestive tract (UADT) cancer. A total of 46 cases, including 13 squamous cell carcinoma (SCC), 11 carcinoma-in situ or dysplasia, and 22 morphologically normal oral biopsies, were analyzed for loss of heterozygosity (LOH) at 9p21, 3p21, and 17p13(TP53) by microsatellite analysis. LOH at one or more tested markers in at least one biopsy was detected in 76% (35 of 46) cases. All of the SCC and carcinoma-in situ cases showed LOH, and, strikingly, more than one-half (69%, 13 of 22) of morphologically normal epithelia also harbored LOH in at least one tested marker. The most frequent LOH was found on chromosome 9p21 (69%, 31 of 45). LOH was observed at 3p21, 17p13(TP53), or in multiple chromosomal arms significantly more often in SCC than in normal epithelia. In the majority of cases, two oral biopsies, one from an OraTest-staining positive area and another from a negative area adjacent to the stain, were collected. Among 25 LOH positive cases with two biopsies, identical allelic losses were confirmed between stained and nonstained biopsies in 16 cases. In the remaining nine cases with discordant LOH patterns between two biopsies, eight cases showed LOH at more genetic loci in OraTest-stained areas. Our data confirm that clonal genetic alterations, especially 9p21 deletion, are often present in the oral epithelia of patients with previous UADT malignancy and, combined with previous studies, suggest that genetic analysis will help stratify patients at risk of developing a secondary oral cancer. In addition to detecting cancer, our study suggests that OraTest can detect clinically occult lesions in the progression pathway to oral cancer.
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PMID:Allelic losses in OraTest-directed biopsies of patients with prior upper aerodigestive tract malignancy. 1144 11

Ductal breast carcinoma in situ (DCIS) is regarded as a precursor to invasive breast cancer. The progression from in situ to invasive cancer is however little understood. We compared some tumour markers in invasive and in situ breast carcinomas trying to find steps in this progression. We designed a semi-experimental setting and compared histopathological grading and tumour marker expression in pure DCIS (n = 194), small invasive lesions (n = 127) and lesions with both an invasive and in situ component (n = 305). Grading was done according to the Elston-Ellis and EORTC classification systems, respectively. Immunohistochemical staining was conducted for p53, c-erbB-2, Ki-67, ER, PR, bcl-2 and angiogenesis. All markers correlated with grade rather than with invasiveness. No marker was clearly associated with the progression from in situ to invasiveness. The expression of tumour markers was almost identical in the 2 components of mixed lesions. DCIS as a group showed a more 'malignant picture' than invasive cancer according to the markers, probably, due to a higher proportion of poorly differentiated lesions. The step between in situ and invasive cancer seems to occur independently of tumour grade. The results suggest that well-differentiated DCIS progress to well-differentiated invasive cancer and poorly differentiated DCIS progress to poorly differentiated invasive cancer.
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PMID:Tumour markers in breast carcinoma correlate with grade rather than with invasiveness. 1155 39

The main reason for the recent interest in p53 is that almost 50% of human cancers contain p53 gene mutations. The majority of studies on p53 alterations in breast cancer have been limited to the isolated cases of ductal carcinoma in situ and infiltrating ductal carcinoma. The aims of this study were to determine the status and timing of p53 mutation in the progression from atypical ductal hyperplasia to invasive cancer, and to evaluate the patterns of p53 mutations in noninvasive and invasive lesions. Available lesions of invasive (n=88) and noninvasive (n=76) lesions were microdissected in 107 paraffin-embedded tissues (19 ductal carcinomas in situ, 57 invasive carcinomas with intraductal components, and 31 pure invasive carcinomas) and double-strand DNA sequencing was performed in exon 4-9 of the p53 gene. Among in situ cancers without invasive disease 36.8% had p53 mutations whereas in situ cancer with concurrent invasive disease showed p53 mutations in 33.3% of cases. In particular, two of seven atypical ductal hyperplasias harbored p53 alterations (one insertion and one missense mutation) in exon 8. The invasive component harbored p53 mutations in 30 of 88 cases (34.1%). We also discovered a novel deletion of 14 bp in exon 6 of two invasive lesions. The invasive component (1.33+/-0.13) carried a greater number of p53 mutations than its counterparts (1.19+/-0.10) and demonstrated more frequent multiple mutations (23.3% vs. 15.4%), but without statistical significance. Moreover, no statistical significance could be attached to the mutation frequency in the zinc-binding domains (26.7% vs. 15.4%), the directly DNA contact region (13.3% vs. 15.4%) and the missense mutation of p53 (50.0% vs. 57.7%) of the two groups. Based on our results, in spite of the small number of the lesions investigated, p53 mutation can occur at the stage of atypical ductal hyperplasia. The hypermutability and the specific p53 mutations involving the biologically functional domain (e.g., zinc binding domain or DNA contact region) have an insignificant influence on invasive progression in the breast cancer.
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PMID:The timing and characterization of p53 mutations in progression from atypical ductal hyperplasia to invasive lesions in the breast cancer. 1171 68

The absence of the tumor suppressor gene p53 confers an increased tumorigenic risk for mammary epithelial cells. In this report, we describe the biological and genetic properties of the p53 null preneoplastic mouse mammary epithelium in a p53 wild-type environment. Mammary epithelium from p53 null mice was transplanted serially into the cleared mammary fat pads of p53 wild-type BALB/c female to develop stable outgrowth lines. The outgrowth lines were transplanted for 10 generations. The outgrowths were ductal in morphology and progressed through ductal hyperplasia and ductal carcinoma in situ before invasive cancer. The preneoplastic outgrowth lines were immortal and exhibited activated telomerase activity. They are estrogen and progesterone receptor-positive, and aneuploid, and had various levels of tumorigenic potential. The biological and genetic properties of these lines are distinct from those found in most hyperplastic alveolar outgrowth lines, the form of mammary preneoplasia occurring in most traditional models of murine mammary tumorigenesis. These results indicate that the preneoplastic cell populations found in this genetically engineered model are similar in biological properties to a subset of precurser lesions found in human breast cancer and provide a unique model to identify secondary events critical for tumorigenicity and invasiveness.
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PMID:Biological and genetic properties of the p53 null preneoplastic mammary epithelium. 1196 32

The purpose of the present study was to carry out multivariate analysis of the effect of the expression of estrogen and progesterone receptors, p53, proliferative antigen (Ki67) and c-erbB-2 on 5-year survival in patients with invasive breast carcinoma concomitant with ductal carcinoma in situ. Material for study consisted of tissue specimens obtained from 48 patients undergoing modified Patey's mastectomy between 1991 and 1998. Univariate analysis revealed that the variables significantly affecting survival were tumour size on gross examination and the level of estrogen and progesterone receptors in the cells of invasive ductal carcinoma of the breast (for the level of significance p = 0.05). The Cox regression model revealed that the only independent variable having a significant effect on survival was the level of estrogen receptors in invasive cancer cells.
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PMID:Prognostic significance of selected immunohistochemical parameters in patients with invasive breast carcinoma concomitant with ductal carcinoma in situ. 1201 22

In the multistep progressive pathogenesis of human breast cancer, comedo ductal carcinoma in situ (DCIS) represents a preinvasive precursor lesion for therapy resistant invasive cancer. Human tissue derived cell culture models exhibiting molecular similarities to clinical DCIS facilitate an important preclinical mechanistic approach for evaluation of preventive efficacy of natural and synthetic chemopreventive compounds. Natural phytochemicals present in fresh fruits, vegetables and grain products are likely to offer protection against cancer. The clinical efficacy of these natural phytochemicals, however, depends on extrapolation, and is therefore equivocal. The present study determined whether the natural soy isoflavone genistein (GEN) inhibited aberrant proliferation in 184-B5/HER cells (a model for human comedo DCIS) and identified possible mechanisms responsible for its efficacy. Human reduction mammoplasty derived HER-2/neu oncogene expressing preneoplastic 184-B5/HER cells represented the experimental system. Flow cytometry and cellular epifluorescence based assays were utilized to quantitate the alterations in cell cycle progression, cellular apoptosis, and in the status of cell cycle regulatory and apoptosis-associated gene product expression. The 184-B5/HER cells exhibited specific immunofluorescence to p185HER, p53, EGFR, but not to ERalpha, thus resembling comedo DCIS. Treatment of 184-B5/HER cells with GEN resulted in a dose-dependent decrease in the viable cell population, increase in the G0/G1:S + G2/M ratio and enhancement of sub G0/G1 (apoptotic population). Exposure to the maximum cytostatic 10 microM dose of GEN down-regulated HER-2/neu mediated signal transduction as evidenced by a 73.9% decrease (p=0.001) in p185HER specific, and a 89.8% decrease (p=0.001) in phosphotyrosine specific immunofluorescence. The increase in G0/G1:S + G2/M ratio in response to the treatment with 10 microM GEN was associated with a 85.5% decrease (p=0.001) in immunoreactivity to PCNA and a 128.6% increase (p=0.004) in immunoreactivity to the cyclin dependent kinase inhibitor p16INK4. The induction of apoptosis by GEN was associated with a 52.8% decrease (p=0.001) in the immunoreactivity to antiapoptotic Bcl-2 and with a 195.9% (p=0.001) increase in the immunoreactivity to proapoptotic Bax. Thus, preventive efficacy of GEN in HER-2/neu+/ER- 184-B5/HER cells may be due to its ability to down-regulate HER-2/neu mediated signal transduction, increase the expression of the cyclin dependent kinase inhibitor p16INK4, and induce Bcl-2 dependent apoptosis. These data provide evidence that GEN may be a potential chemopreventive lead compound for human comedo DCIS. The 184-B5/HER cells, may therefore, provide a high throughput mechanistic bioassay to identify new chemopreventive agents for human breast cancer.
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PMID:Soy isoflavone genistein modulates cell cycle progression and induces apoptosis in HER-2/neu oncogene expressing human breast epithelial cells. 1223 20

Invasive cervical cancer remains a leading cause of morbidity and mortality, especially among women in the developing world where screening is either deficient or absent. Of all agents linked to the causation of this disease, high-risk human papillomavirus (HPV) appears to be the strongest factor. However, not all women with HPV develop cervical cancer. Steroid contraception has been postulated to be one mechanism whereby HPV exerts its tumorigenic effect on cervical tissue. Steroids are thought to bind to specific DNA sequences within transcriptional regulatory regions on the HPV DNA to either increase or suppress transcription of various genes. Although some earlier studies were reassuring as no increased incidence of cervical cancer was observed, subsequent research has shown a causative association, especially among long-term users. The role of steroids was further enhanced by the discovery of hormone receptors in cervical tissue. Some earlier studies of oral contraceptive steroids found no increased risk, even after controlling for other risk factors, including smoking and number of partners. However, prospective studies have shown a greater progression of dysplasia to carcinoma-in-situ with more than 6 years of oral steroid contraceptive use. Similar findings were also evident from other work, including the Royal College of General Practitioners Oral Contraception Study. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives showed a relative risk of 1.2 for invasive cancer in users of the long-acting progestational contraceptive, depo-medroxyprogesterone acetate. However, in users of more than 5 years duration, an estimate of 2.4 was reported. The upstream regulatory region (URR) of the HPV type 16 viral genome, mediates transcriptional control of the HPV genome and is thought to contain enhancer elements that are activated by steroid hormones. It has been shown that steroid hormones bind to specific glucorticoid-response elements within HPV-DNA. Experimental evidence has revealed that high-risk type HPV 16 are able to stimulate the development of vaginal and cervical squamous cell carcinomas in transgenic mice exposed to slow-release pellets of 17 beta-estradiol in the presence of human keratin-14 promoter. Squamous cell carcinomas developed in a multi-stage pathway only in transgenic mice and not in nontransgenic mice. The E6 oncoprotein of HPV 16 has been shown to bind to the p53 tumor suppressor gene and stimulate its degradation by a ubiquitin-dependent protease system. Steroid hormones are thought to increase the expression of the E6 and E7 HPV 16 oncogenes, which in turn bind to and degrade the p53 gene product, leading to apoptotic failure and carcinogenesis. However, the molecular basis of this remains to be proven.
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PMID:The role of steroid contraceptive hormones in the pathogenesis of invasive cervical cancer: a review. 1265 8

Association of infection with papillomavirus and dysplasia of the cervix uteri has been firmly established. There are only few cervical cancers where no HPV DNA is detectable. The mechanism of epithelial cell immortalization by interaction with tumour suppressor genes p53 and pRb by viral oncogenes E6 and E7 is elucidated. Progression of the HPV infected cell to a malignant phenotype involves further modification of host gene expression and/or mutations. The appearance of chromosomal aberrations can lead to mutational inactivation or loss of tumour suppressor genes (TSG), activation and amplification of oncogenes, with importance for the process of carcinogenesis. Oncogene amplification, with exception of few reports, seems not to be a major mechanism in cervical carcinogenesis. In contrast, cytogenetic and loss of heterozygosity (LOH) results from CIN and invasive cancer demonstrate alterations at specific chromosomal regions, pointing at localisation of TSG. Genetic alterations at chromosomes 3p, 6p, 1lq were frequently found early in tumour development Primary invasive carcinoma showed additional allelic losses at chromosome arms 6q, 17p and 18q. Useful biological diagnostic and prognostic markers for high-risk HPV infection and malignant progression may be p16NK4 p27Kip, and NET-I/C4.8. Putative senescence genes relevant for HPV-induced carcinogenesis are localized on chromosomes 2, 4 and 10. Genes for Telomerase suppression are presumably located on chromosomes 3, 4 and 6. Natural immune responses to HPV infection exist Therefore, immune therapy is an attractive possibility for prevention and therapy of HPV infection. To date, vaccine development has reached clinical evaluation. Prophylaxis aims at the induction of virus neutralizing antibodies to capsid proteins. Virus-like particle vaccines are currently tested in clinical trials. Due to the long lag period between infection and clinical manifestation trials will take a long time until conclusive results are obtained. Mandatory expression of viral and perhaps certain cellular genes in infected epithelial and tumour cells offers targets for therapeutic approaches. Since most dysplasia clears spontaneously the viral infection is immunogenic to some extent. However, in some individuals the immune response has to be stimulated by vaccination in order to be effective. Several strategies are being tested in clinical trials and others are in preclinical development The task will be to circumvent immunosuppressive features of the HPV infected cells.
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PMID:HPV induced cervical carcinogenesis: molecular basis and vaccine development. 1279 44

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