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 hormonal milieu at time of tumor surgery seems to have a significant impact on survival in premenopausal breast cancer patients. Indeed, surgery performed during the follicular phase of the menstrual cycle was suggested to correlate with a poor prognosis. To investigate the relationship between prognosis and menstrual cycle at time of surgery, we analyzed the expression of some markers associated with tumor aggressiveness, such as the hormone receptors, HER2, p53, Bcl2, and cathepsin D in breast carcinomas obtained from 198 premenopausal women who underwent surgery during different phases of the menstrual cycle. HER2 overexpression was found to fluctuate in hormone receptor-positive tumors. In actual fact, 20% of the tumors removed during the follicular phase scored HER2-positive, versus 8% of those removed during the luteal phase. Similarly, a number of hormone receptor-positive tumor specimens, obtained from the same patients during follicular and luteal phases, were scored HER2-positive when the sample was removed during the follicular phase and HER2-negative when removed in the luteal phase. Southern blot analysis of the HER2 gene indicated that, in hormone receptor-positive cases, the overexpression of HER2 is often not associated with gene amplification. The finding that overexpression of the HER2 gene, associated with tumor aggressiveness, can fluctuate according to the hormonal milieu may explain the increased survival of patients operated during the luteal phase. It is also relevant to the selection and treatment of patients most likely to benefit from anti-HER2 antibody therapy.
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PMID:Fluctuation of HER2 expression in breast carcinomas during the menstrual cycle. 1055 Mar 11

The new anticancer agent poly(L-glutamic acid)-paclitaxel (PG-TXL) is a conjugate of paclitaxel and the water-soluble polyglutamate carrier. The observation that PG-TXL appears to possess antitumor activity superior to free paclitaxel in preclinical studies suggests that PG-TXL might possess favorable pharmacokinetic properties and/or have a mechanism of action different from that of paclitaxel. The purpose of this study was to compare the pharmacological action of PG-TXL and free paclitaxel in a panel of breast cancer cell lines with emphasis on their ability to induce apoptosis, their effects on cell cycle progression, and their cellular uptake. Morphological analysis and biochemical characterizations demonstrated that both compounds have similar abilities to induce apoptosis in cells expressing wild-type p53 (MCF-7) or mutant p53 (MDA-MB435 and MDA-MB453). Although MCF-7 cells were less sensitive to each compound than MDA-MB435 and MDA-MB453 cells, transfection experiments demonstrated that p53 did not appear to play a significant role in drug-induced cell death with either agent. Flow cytometry analysis further revealed that both free paclitaxel and PG-TXL induced a characteristic G2/M arrest in the cell cycle, consistent with the disturbance of microtubule polymerization as their mechanism of action. Western blot analysis showed that paclitaxel and PG-TXL downregulated HER2/neu expression in a similar fashion. HPLC analysis revealed that paclitaxel was released from the PG-TXL conjugate in vitro. The released paclitaxel, not the glutamic acid polymer, was subsequently transported into the cells. These results suggest that PG-TXL exerts its anticancer activity by continuous release of free paclitaxel, and that the favorable pharmacokinetics and drug distribution of the PG-TXL conjugate in vivo are likely the main factors contributing to its superior anticancer activity.
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PMID:Comparison of action of paclitaxel and poly(L-glutamic acid)-paclitaxel conjugate in human breast cancer cells. 1060 57

Apart from the regulation of calcium metabolism, 1, 25-dihydroxyvitamin D(3) plays an essential role in cell proliferation and differentiation in several tissues. The vitamin D receptor (VDR) gene shows polymorphisms in humans that appear to be clinically significant in some pathological conditions. In the present study, the BsmI polymorphism of the VDR gene was studied in 59 Caucasian patients with rectal cancer (mean follow-up: 48 months). The relationship between VDR genotypes and the expression of oncogenes as well as their influence on survival were also investigated. VDR polymorphism was examined in tumor and normal mucosa cells by PCR technique. The expression of erbB-2/HER-2, p53, ras and epidermal growth factor receptor (EGFR) was also detected by immunohistochemistry and protein blotting. The presence of the VDR B allele significantly correlated with the overexpression of the erbB-2 oncogene. There was no difference in the VDR genotype between cancer and normal mucosal cells. Coexpression of erbB-2, pan-ras, p53 and EGFR internal and external domains was significantly higher in cancer cells than in normal mucosa. There was no significant correlation between VDR genotypes and age, gender, tumor infiltration depth, number and site of lymph node metastases and lymphatic or blood vessel infiltration. The VDR genotype alone did not influence survival. Overexpression of erbB-2 and EGFR was associated with a poor prognosis. In patients expressing only one oncogene in cancer cells, the presence of the VDR B allele showed a tendency to a poor prognosis. In conclusion, VDR gene BsmI polymorphism might affect the development and prognosis of rectal cancer by influencing erbB-2 oncogene expression.
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PMID:Vitamin D receptor gene BsmI polymorphism correlates with erbB-2/HER-2 expression in human rectal cancer. 1076 27

Pancreatic cancer is a lethal disease characterized by local invasion and early dissemination. It is resistant to conventional surgical, radiotherapeutic, and chemotherapeutic modalities. These interventions have had minimal impact on overall survival with very few patients enjoying long term survival. Over the past few years, 2'difluoro-2'deoxycytidine (gemcitabine) has demonstrated modest activity in this disease and investigations are proceeding to expand its role in combination with radiotherapy and other chemotherapeutic agents. In addition, the identification of the molecular defects underlying this disease has suggested molecular targets for the design of rational systemic therapy. These targets include matrix metalloproteinases, K-ras, HER2/neu, p53, and the epidermal growth factor receptor. Current and future clinical trials designed to improve the survival of patients with pancreatic cancer will be discussed.
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PMID:Current approaches and future strategies for pancreatic carcinoma. 1083 Jan 40

A new cell line, designated HDQ-P1, was successfully established from a primary ductal infiltrating mammary carcinoma by using a 3T3 feeder layer lethally irradiated to 60 Gy. The HDQ-P1 cells have been grown in culture for over 115 passages and have a doubling time of 60 hours. Characterization of the cell line was performed. This included morphology by light and transmission electron microscopy, karyotype, growth rate, telomerase expression, tumor antigen expression, xenograft implantation into nude mice, colony formation in soft agar, TP53 sequencing, and gene copy number of C-MYC, C-ERBB-2, and C-H-RAS oncogenes. The epithelial nature of this cell line was confirmed by ultrastructural analysis, expression of cytokeratins, and epithelial membrane antigen. The HDQ-P1 cells possess an extensively rearranged and polyploid karyotype, with an average of 20 recurrent marker chromosomes. Scatchard analysis demonstrated that both primary tumor and HDQ-P1 cells were estrogen- and progesterone-receptor negative. The HDQ-P1 cells had the same expression of human telomerase reverse transcriptase as other established breast cancer cell lines such as MDA-MB-231, SK-BR-3, and MCF-7. Direct DNA sequencing showed a point mutation which yielded to a stop codon at the amino acid 213 in exon 6 of the TP53 gene. A five-fold amplification of C-MYC was observed in HDQ-P1 cells. No amplification of C-ERBB-2 and C-H-RAS genes were observed. This cell line presents unique characteristics and may prove to be a good experimental model for investigating breast cancer biology.
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PMID:Establishment and characterization of a new cell line derived from a human primary breast carcinoma. 1091 78

No reliable pathologic criteria have been identified that predict clinical behavior in adrenal and extra-adrenal pheochromocytomas (PHEOs). Reliable prognostic markers for the prediction of clinical outcome are needed to assign optimal treatment for potentially malignant tumors. In this report, we evaluated several molecular markers (topoisomerase II alpha, E-cadherin, HER-2/neu, and retinoblastoma (RB) gene protein) that have not been previously studied in PHEOs. Paraffin-embedded, formalin-fixed tissue blocks from 50 cases of PHEO (30 benign and 20 malignant, 31 adrenal and 19 extra-adrenal) were obtained from University of Utah Health Sciences Center, Salt Lake City, and the Medical College of Wisconsin, Milwaukee. Gross (tumor size, weight, local extension, cyst formation, hemorrhage, necrosis), microscopic (pleomorphism, hyaline globules, intranuclear inclusion, mitotic count, capsular and vascular invasion, ganglionic/neuronal differentiation), and immunohistochemical features (topoisomerase II alpha, p53, MIB-1, E-cadherin, RB, and HER-2/neu) were studied. With the exception of vascular invasion (P = 0.025), there were no unequivocal gross or microscopic characteristics that distinguished benign from malignant lesions (P approximately = 0.11-0.71). Topoisomerase III and MIB-1 indices in malignant lesions were significantly higher than those observed in benign lesions (P = 0.012 and 0.019). Differences in p53 expression were not statistically significant (P = 0.082). Loss in RB protein product expression was significantly more common in malignant lesions (P = 0.001), E-cadherin loss and HER-2/-neu overexpression were not observed in any of the benign or malignant lesions. We studied the immunohistochemical expression of topoisomerase II alpha, MIB-1, p53, RB gene protein product, E-cadherin, and HER-2/neu in a series of adrenal and extra-adrenal PHEOs. Overexpression of topoisomerase II alpha and MIB-1 and loss of RB protein product were more common in malignant lesions, whereas p53, E-cadherin, and HER-2/neu do not seem to have diagnostic utility in the prediction of biologic behavior in these neoplasms.
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PMID:Prognostic value of immunohistochemical expression of topoisomerase alpha II, MIB-1, p53, E-cadherin, retinoblastoma gene protein product, and HER-2/neu in adrenal and extra-adrenal pheochromocytomas. 1112 18

Three-dimensional tumor growth is dependent on the perpetual recruitment of host blood vessels to the tumor site. This recruitment process (mainly via angiogenesis) is thought to be triggered, at least in part, by the very same set of genetic alterations (activated oncogenes, inactivated/lost tumor suppressor genes) as those responsible for other aspects of malignant transformation (e.g., aberrant mitogenesis, resistance to apoptosis). Potent oncogenes are able to deregulate expression of both angiogenesis stimulators and inhibitors in cancer cells. For example, mutant ras expression is associated with increased production of vascular endothelial growth factor (VEGF) and downregulation of thrombospondin-1 (TSP-1). Upregulation of VEGF and angiogenesis can also be induced by constitutive activation of other oncogenic proteins (e.g., EGFR, Raf, MEK, PI3K) acting at various levels on the Ras signaling pathway. The mode and the magnitude of such proangiogenic influences can be significantly modified by cell type (fibroblastic or epithelial origin), epigenetic factors (hypoxia, changes in cell density), and/or presence of additional genetic lesions (e.g., preceding loss of p16 or p53 tumor suppressor genes). Activated oncogenes (e.g., ras, src, HER-2) induce co-expression of angiogenic properties concomitantly with several highly selectable traits (increased mitogenesis, resistance to apoptosis), a circumstance that may accelerate selection of the angiogenic phenotype at the cell population level. On the other hand oncogene-induced reduction in growth requirements may also endow tumor cells with a diminished (albeit not abrogated) dependence on (close) proximity to blood vessels, i.e., with reduced vascular dependence. Thus, oncogenes can impact several interconnected aspects of cellular growth, survival, and angiogenesis. Experimental evidence suggests that, in principle, many of these properties (including angiogenesis) can be simultaneously suppressed (and tumor stasis or regression induced) by effective use of the specific oncogene antagonists and signal transduction inhibitors.
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PMID:Oncogenes and angiogenesis: signaling three-dimensional tumor growth. 1114 71

We have investigated primary ductal carcinomas in situ (DCIS) of the breast and their local recurrences after breast-conserving therapy (BCT) for histological characteristics and marker expression. Patients who were randomized in the EORTC trial 10853 (wide local excision versus excision plus radiotherapy) and who developed a local recurrence were identified. Histology was reviewed for 116 cases; oestrogen and progesterone receptor status, and HER2/ neu and p53 overexpression were assessed for 71 cases. Comparing the primary DCIS and the invasive or non-invasive recurrence, concordant histology was found in 62%, and identical marker expression in 63%. Although 11% of the recurrences developed at a distance from the primary DCIS, nearly all these showed the same histological and immunohistochemical profile. 5 patients developed well-differentiated DCIS or grade I invasive carcinoma after poorly differentiated DCIS. Although these recurrences occurred in the same quadrant as the primary DCIS, they may be considered as second primary tumours. Only 4 patients developed poorly differentiated DCIS or grade III invasive carcinoma after well differentiated DCIS. We conclude that in most cases the primary DCIS and its local recurrence are related histologically or by marker expression, suggesting that local recurrence usually reflects outgrowth of residual DCIS; progression of well differentiated DCIS towards poorly differentiated DCIS or grade III invasive carcinoma is a non-frequent event.
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PMID:Histological type and marker expression of the primary tumour compared with its local recurrence after breast-conserving therapy for ductal carcinoma in situ. 1120 51

The gene for the steroid receptor coactivator amplified in breast cancer 1 (AIBI), located on chromosome 20q12, is overexpressed at the mRNA level in up to 60% of primary breast carcinomas; however, only 5% of these tumors show DNA amplification. The transcription factors and signaling pathways relevant to breast cancer, which in the absence of DNA amplification are responsible for and targeted by elevated levels of AIBI mRNA, are unknown. In the present study, in situ hybridization was used to examine AIB1 mRNA expression in 93 breast carcinomas of varying histological grade and immunohistochemical profile. AIB1 mRNA was overexpressed relative to normal breast tissue in 26 of 83 (31%) invasive tumors. This was found to associate with high tumor grade (P = 0.0006), lack of immunohistochemical staining for the steroid receptors estrogen receptor (P = 0.002) and progesterone receptor (P = 0.002), and strong protein staining for p53 (P = 0.01) and HER2/neu (P = 0.002). These findings suggest that AIB1 overexpression may impact on breast cancer by a mechanism not wholly dependent on steroid receptor coexpression and which may involve other oncogenic events, such as p53 protein stabilization and HER2/neu overexpression.
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PMID:Overexpression of the steroid receptor coactivator AIB1 in breast cancer correlates with the absence of estrogen and progesterone receptors and positivity for p53 and HER2/neu. 1122 79

Breast tumor development and progression are thought to occur through a complex, multistep process, including oncogene activation (eg HER2/neu) and mutation or loss of tumor suppressor genes (eg p53). Determining the function of genetic alterations in breast carcinoma tumorigenesis and metastasis has been the focus of intensive research efforts for several decades. One group of proteins that play a critical role in breast cancer cell signaling pathways are tyrosine kinases. Overexpression of the tyrosine kinase HER2/neu is observed in many human breast cancers and is positively correlated with enhanced tumorigenesis. Recently, another tyrosine kinase, Syk, has been implicated as an important inhibitor of breast cancer cell growth and metastasis. This recent finding was unexpected, since Syk function has been predominantly linked to hematopoietic cell signaling, and is discussed further in this commentary.
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PMID:Syk: a new player in the field of breast cancer. 1125 Jul 39


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