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)

The aim of this study is to analyse whether immunohistochemistry (IHC) applying a broad set of markers could be used to categorise ductal carcinoma in situ (DCIS) of the breast in distinct subgroups corresponding to the recently defined molecular categories of invasive carcinoma. Immunohistochemistry of pure DCIS cases constructed in tissue arrays was performed with 16 markers (oestrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), Bcl-2, p53, Her2, insulin-like growth factor receptor, E-cadherin, epithelial membrane antigen (EMA), CA125, keratins 5/6, 14, 19, epidermal growth factor receptor, S100, and CD31). Results in 163 cases were analysed by unsupervised hierarchical clustering. Histological classification was performed by review of whole tissue sections and identified 36 well-, 55 intermediately, and 72 poorly differentiated DCISs. Unsupervised hierarchical cluster analysis categorised DCIS into two major groups that could be further subdivided into subgroups based on the expression of six markers (ER, PR, AR, Bcl-2, p53, and Her2). In the major predominantly ER/Bcl-2-positive (luminal) group, three subgroups (AR-positive (n=33), AR-negative (n=40), and mixed (n=34)) could be identified and included 34 well-differentiated DCISs. Within the major predominantly ER/Bcl-2-negative (nonluminal) group, a Her2-positive subgroup (n=34) was characterised by 31 poorly differentiated lesions. Eight triple-negative lesions, including one positive for keratin 5/6 and two positive for p53, were encountered. Intermediately differentiated DCIS shared a comparable IHC staining pattern with well-differentiated DCIS that was distinct from poorly differentiated DCIS (P<0.001). Ductal carcinoma in situ could be categorised by IHC into two major groups and five subgroups using six markers. Morphologically, intermediately differentiated DCIS seems to have more biological similarities with well-differentiated lesions as compared to poorly differentiated lesions.
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PMID:Immunohistochemical categorisation of ductal carcinoma in situ of the breast. 1804 78

Previous studies have shown conflicting results on prognostic significance of basal-like breast tumors, but hormone receptor is a confusing factor in most of the prognostic evaluations. We aimed to characterize the prognostic features of basal-like tumors without the influence of hormone receptor status in a series of hormone receptor-negative breast tumors. Using tissue microarray and immunohistochemistry methods, according to the expression of HER2 and basal markers (CK5/6, CK14, EGFR), we categorized 713 consecutive hormone receptor-negative invasive breast cancers into 3 subtypes: HER2 (HER2+), basal-like (HER2-, any basal marker+), and null (HER2-, all basal markers-). The HER2 phenotype was subdivided into pure-HER2 (HER2+, all basal markers-) and basal-HER2 (HER2+, any basal marker+) subgroups. Expression of p53, p63, vimentin, and BRCA1 was assessed immunochemically. Basal-like tumors showed significantly higher grade, more frequent recurrence, and higher expression of vimentin and p63 than HER2 and null phenotypes. Basal-HER2 phenotype had significantly younger mean age and expressed a higher level of p53 and vimentin like basal-like and/or HER2 phenotypes. However, unlike all the other hormone receptor-negative phenotypes, they highly expressed BRCA1. No significant difference was found in 5-year survival among basal-like and the other hormone receptor-negative phenotypes, except for basal-HER2, which showed poorer 5-year overall survival than basal-like tumors. In conclusion, although basal-like breast tumors have distinct clinicopathologic and immunohistochemical features, they have similar 5-year survival compared with the other hormone receptor-negative tumors including HER2 and null phenotypes. However, there exists a small group of hormone receptor-negative tumors expressing HER2 and basal markers simultaneously. This small group of tumors showed significantly poorer 5-year overall survival than basal-like breast tumors and might require different treatment strategy.
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PMID:Basal-HER2 phenotype shows poorer survival than basal-like phenotype in hormone receptor-negative invasive breast cancers. 1804 47

Microglandular adenosis (MGA) of the breast is widely known as a benign lesion that can mimic invasive carcinoma. In situ and invasive carcinomas have been described as arising in MGA, but which cases of MGA will progress to carcinoma is unclear. Criteria for distinguishing uncomplicated MGA, MGA with atypia (AMGA), and carcinoma arising in MGA (MGACA) are not standardized. The primary objective of this study was to illustrate the clinical, histopathologic, and immunophenotypical characteristics of MGA, AMGA, and MGACA in an effort to provide criteria for distinguishing the 3 types. We retrospectively identified 108 cases seen at M.D. Anderson Cancer Center between 1983 and 2007 that had a diagnosis of MGA. Of the 108 cases, 65 cases had available material for review. Inclusion criteria were glands of MGA expressing S-100 protein and lacking myoepithelial layer (smooth muscle actin negative). Eleven out of 65 cases qualified to have an MGA component; myoepithelial layer was detected in the remaining 54 cases and were classified as adenosis. Out of the 11 MGA patients, there were 3 patients with uncomplicated MGA, 2 had AMGA, and 6 had MGACA. Staining indices for the cell cycle markers p53 and Ki-67 were used to compare the 3 tumor categories. Additional staining for other tumor markers [estrogen and progesterone receptors, HER2, epidermal growth factor receptor (EGFR), c-kit, CK5/6, and CK18] were performed. Patient demographics, tumor radiologic features, and clinical follow-up data were collected for all cases. Multiple invasive histologic components were identified in each of the MGACA cases. All invasive MGACAs had a duct-forming component. In addition, basal-like component was present in 2 cases, aciniclike in 2, matrix producing in 4, sarcomatoid in 1, and adenoid cystic in 1. All tumors had strong and diffuse CK8/18 and EGFR expression but no estrogen receptor, progesterone receptor, HER2 (ie, triple negative), or CK5/6 expression. C-kit was focally expressed in 2 of the MGACAs. Ki-67 and p53 labeling indices was < 3% in all MGAs, 5% to 10% in the AMGAs, and > 30% in MGACAs. In a follow-up ranging from 14 days to 8 years, none of the MGA cases recurred. One of the AMGA cases recurred as invasive carcinoma in a background of AMGA after 8 years following incomplete excision of the lesion. Three out of 6 MGACA cases (50%) required multiple consecutive resections ending up with mastectomy due to involved margins by invasive or in situ carcinoma. Two out of 6 MGACA cases (34%) developed metastasis and died of disease. Our data showed that Ki-67 and p53 expression, in conjunction with the morphologic features, could be a reliable marker to distinguish MGA from AMGA and MGACA. Although 11 tumors were only included in our study, 64% of the tumors were carcinomas arising in MGA. This high incidence of MGACA may not represent the actual frequency of MGAs progressing into carcinoma and is likely due to referral bias in our institution. Nonetheless, the high association of carcinoma with MGA necessitates complete excision of MGA to rule out invasion. Although all the MGACA cases were triple negative and express EGFR (basal-like features), all the cases in our study showed a luminal type of differentiation by CK8/18 expression, indicating that MGACA may not fit well into the current proposed molecular classification of breast cancer.
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PMID:Clinical, histopathologic, and immunohistochemical features of microglandular adenosis and transition into in situ and invasive carcinoma. 1830 Jul 93

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

Tissue microarray (TMA) technology has been developed to facilitate high-throughput immunohistochemical and in situ hybridization analysis of tissues by inserting small tissue biopsy cores into a single paraffin block. Several studies have revealed novel prognostic biomarkers in esophageal squamous cell carcinoma (ESCC) by means of TMA technology, although this technique has not yet been validated for these tumors. Because representativeness of the donor tissue cores may be a disadvantage compared to full sections, the aim of this study was to assess if TMA technology provides representative immunohistochemical results in ESCC. A TMA was constructed containing triplicate cores of 108 formalin-fixed, paraffin-embedded squamous cell carcinomas of the esophagus. The agreement in the differentiation grade and immunohistochemical staining scores of CK5/6, CK14, E-cadherin, Ki-67, and p53 between TMA cores and a subset of 64 randomly selected donor paraffin blocks was determined using kappa statistics. The concurrence between TMA cores and donor blocks was moderate for Ki-67 (kappa = 0.42) and E-cadherin (kappa = 0.47), substantial for differentiation grade (kappa = 0.65) and CK14 (kappa = 0.71), and almost perfect for p53 (kappa = 0.86) and CK5/6 (kappa = 0.93). TMA technology appears to be a valid method for immunohistochemical analysis of molecular markers in ESCC provided that the staining pattern in the tumor is homogeneous.
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PMID:Validation of tissue microarray technology in squamous cell carcinoma of the esophagus. 1839 48

Women with germ-line mutations of the BRCA1 tumor suppressor gene are highly susceptible to breast and ovarian cancer. The protein product of BRCA1 is involved in a broad spectrum of biological processes and interacts with many diverse proteins. One of these, BARD1, associates with BRCA1 to form a heterodimeric complex that is enzymatically active as an ubiquitin E3 ligase. Although the BRCA1/BARD1 heterodimer has been implicated in several aspects of BRCA1 function, its role in tumor suppression has not been evaluated. To address this question, we generated mouse strains carrying conditional alleles of either Bard1 or Brca1 and used Cre recombination to inactivate these genes in mammary epithelial cells. Significantly, the conditional Bard1- and Brca1-mutant mice developed breast carcinomas that are indistinguishable from each other (and from those of double conditional Bard1/Brca1-mutant animals) with respect to their frequency, latency, histopathology, and cytogenetic features. Reminiscent of the basal-like breast carcinomas seen in human BRCA1 mutation carriers, these tumors are "triple negative" for estrogen and progesterone receptor expression and HER2/neu amplification. They also express basal cytokeratins CK5 and CK14, have an elevated frequency of p53 lesions, and display high levels of chromosomal instability. The remarkable similarities between the mammary carcinomas of Bard1-, Brca1-, and Bard1/Brca1-mutant mice indicate that the tumor suppressor activities of both genes are mediated through the BRCA1/BARD1 heterodimer.
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PMID:The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression. 1844 92

In order to illustrate the clinical and histological presentations of laryngeal atypical carcinoids and their potential course, we report six cases. We evaluated the factors predictive of local recurrence and metastatic diffusion. For each case, we noted the mitotic index, the quality of the resection, the limits of the tumor and the presence of necrosis. An immunohistochemical study was carried out with a series of antibodies (cytokeratins; D(2)40; CD31; MIB1; P53; P16; TTF1...). The clinical presentation we observed was quite similar to that reported in the literature. These tumors are CK7+, CK8+, CK19+, CK5-6-, CK14- and CK20-. P16 is constantly positive. Only the mitotic index and the lymphatic presence of embolus were correlated with the time course. The tumor is more aggressive when the mitotic index is high and an unfavorable course is observed when there are lymphatic emboli or when the Ki67 index is higher than 5%.
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PMID:[Atypical carcinoid of the arytenoid: report of six cases]. 1853 8

Normal human prostate (NHP) epithelial cells undergo senescence in vitro and in vivo, but the underlying molecular mechanisms remain obscure. Here we show that the senescence of primary NHP cells, which are immunophenotyped as intermediate basal-like cells expressing progenitor cell markers CD44, alpha2beta1, p63, hTERT, and CK5/CK18, involves loss of telomerase expression, up-regulation of p16, and activation of p53. Using genetically defined manipulations of these three signaling pathways, we show that p16 is the primary determinant of the NHP cell proliferative capacity and that hTERT is required for unlimited proliferative life span. Hence, suppression of p16 significantly extends NHP cell life span, but both p16 inhibition and hTERT are required to immortalize NHP cells. Importantly, immortalized NHP cells retain expression of most progenitor markers, demonstrate gene expression profiles characteristic of proliferating progenitor cells, and possess multilineage differentiation potential generating functional prostatic glands. Our studies shed important light on the molecular mechanisms regulating the proliferative life span of NHP progenitor cells.
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PMID:Critical and distinct roles of p16 and telomerase in regulating the proliferative life span of normal human prostate epithelial progenitor cells. 1866 89

A primary invasive micropapillary carcinoma of the breast in a 46-year-old woman is reported. Histologically, it was composed predominantly of papillary tumor cell clusters without fibrovascular cores, surrounded by a clear space. Tumor cells were positive for cytokeratin (CK) 7, estrogen receptor (ER), and progesterone receptor (PR), but negative for p53, CK 20, CD34, c-Erb-B2, CK5, epidermal growth factor receptor (EGFR), vimentin, and c-kit. MUC1 expression was found at the reversed apical membrane of neoplastic cell clusters. Accordingly, electron microscopy showed the lack of basement membrane and presence of microvilli at the basal surface of the tumor cells. Moreover, ultrastructural examination revealed single tumor cell death characterized by patchy condensations of chromatin throughout the nucleus. These nuclear alterations were associated with the occurrence of empty cytoplasmic vacuoles, conferring a necrosis-like phenotype to this cell death. Alternative programmed cell deaths are reviewed and their morphologic distinction is discussed.
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PMID:Micropapillary carcinoma of the breast with necrosis-like cell death: a case report. 1869 1

S100A2 is a homodimeric protein that undergoes oxidative cross-linking and translocation from the nucleus to the cytosol in the context of oxidative stress. Suggestive of a role for S100A2 in the cutaneous response to ultraviolet light, we found altered S100A2 immunostaining in photodamaged human skin, and crosslinking of S100A2 after ultraviolet A (UVA) irradiation of normal human keratinocytes (NHK). Skin from mice, rats, and rabbits did not contain S100A2 protein, whereas skin samples from pigs, frogs and humans were strongly positive. Survival after UVA irradiation was significantly greater in NHK compared to mouse keratinocytes, suggesting a protective role for S100A2. To test this hypothesis in vivo, we expressed S100A2 in SKH2/J hairless mice under the control of a bovine keratin 5 promoter, and compared responses of TG and WT mice from 1 to 7 days after a single dose (0.5-1 MED) of solar-simulated radiation (SSR) from UVA-340 bulbs. WT and TG mice manifested a similarly robust response to SSR, characterized by epidermal hyperplasia, marked induction of p21(WAF), and a twofold increase in p53. Thymine dimers (TD) were markedly increased in the epidermis and the dermis, but while over 95% of the epidermal TD were removed by 5-6 days, elevated dermal TD persisted nearly unchanged for 7 days. Global transcriptional profiling of WT and TG mice revealed strong induction of multiple transcripts, including keratins K6 and K16, defensin beta 3, S100A8, S100A9, Sprr2i and Sprr2f. However, the only S100A2-dependent difference we observed was an induction of Cxcl13 transcripts in TG, but not WT mice (4.4-fold vs. 0.7-fold, n = 3, P = 0.022). This finding was confirmed in an independent set of mice analyzed by quantitative RT-PCR (8.8-fold vs. 1.2-fold, n = 4, P = 0.001). The finding of persistent dermal DNA damage after suberythemal doses of SSR merits further study.
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PMID:Transgenic expression of S100A2 in hairless mouse skin enhances Cxcl13 mRNA in response to solar-simulated radiation. 1877 13


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