Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemotherapeutic drug resistance is a major clinical problem and cause for failure in the therapy of human cancer. One of the goals of molecular oncology is to identify the underlying mechanisms, with the hope that more effective therapies can be developed. Several mechanisms have been suggested to contribute to chemoresistance: 1) amplification or overexpression of the P-glycoprotein family of membrane transporters (eg, MDR1, MRP, LRP) which decrease the intracellular accumulation of chemotherapy; 2) changes in cellular proteins involved in detoxification (eg, glutathione S-transferase pi, metallothioneins, human MutT homologue, bleomycin hydrolase, dihydrofolate reductase) or activation of the chemotherapeutic drugs (DT-diaphorase, nicotinamide adenine dinucleotide phosphate:cytochrome P-450 reductase); 3) changes in molecules involved in DNA repair (eg, O6-methylguanine-DNA methyltransferase, DNA topoisomerase II, hMLH1, p21WAF1/CIP1; 4) activation of oncogenes such as Her-2/neu, bcl-2, bcl-XL, c-myc, ras, c-jun, c-fos, MDM2, p210 BCR-abl, or mutant p53. An overview of these resistance mechanisms is presented, with a particular focus on the role of oncogenes. Some current strategies attempting to reverse their effects are discussed.
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PMID:Role of oncogenes in resistance and killing by cancer therapeutic agents. 909 Apr 98

Thirty percent of human breast cancers have amplification of ERBB2, often in conjunction with mutations in p53. The most common p53 mutation in human breast cancers is an Arg-to-His mutation at codon 175, an allele that functions in a dominant oncogenic manner in tumorigenesis assays and is thus distinct from loss of p53. Transgenic mice expressing mouse mammary tumor virus-driven neu transgene (MMTV-neu) develop clonal mammary tumors with a latency of 234 days, suggesting that other events are necessary for tumor development. We have examined the role of mutations in p53 in tumor development in these mice. We have found that 37% of tumors arising in these mice have a missense mutations in p53. We have directly tested for cooperativity between neu and mutant p53 in mammary tumorigenesis by creating bitransgenic mice carrying MMTV-neu and 172Arg-to-His p53 mutant (p53-172H). In these bitransgenic mice, tumor latency is shortened to 154 days, indicating strong cooperativity. None of the nontransgenic mice or the p53-172H transgenic mice developed tumors within this time period. Tumors arising in the p53-172H/neu bitransgenic mice were anaplastic and aneuploid and exhibited increased apoptosis, in distinction to tumors arising in p53-null mice, in which apoptosis is diminished. Further experiments address potential mechanisms of cooperativity between the two transgenes. In these bitransgenic mice, we have recapitulated two common genetic lesions that occur in human breast cancer and have shown that p53 mutation is an important cooperating event in neu-mediated oncogenesis.
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PMID:neu/ERBB2 cooperates with p53-172H during mammary tumorigenesis in transgenic mice. 915 14

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

Anti-Her-2/neu antibody is known to induce apoptosis in HER-2/neu overexpressing breast cancer cells. However, exact regulatory mechanisms mediating and controlling this phenomenon are still unknown. In the present study, we have investigated the effect of anti-Her-2/neu antibody on apoptosis of HER-2/neu overexpressing human breast cancer cell lines SK-BR-3, HTB-24, HTB-25, HTB-27, HTB-128, HTB-130 and HTB-131 in relation to p53 genotype and bcl-2 status. SK-BR-3, HTB-24, HTB-128 and HTB-130 cells exhibited mutant p53, whereas wild type p53 was found in HTB-25, HTB-27 and HTB-131 cells. All seven cell lines weakly expressed bcl-2 protein (10-20%). Anti-Her-2/neu antibody, irrespective of p53 and bcl-2 status, induced apoptosis in all 7 cell lines dose- and time-dependently and correlated with Her-2/neu overexpression. In addition, incubation of cell lines with anti-Her-2/neu antibody did not alter p53 or bcl-2 expression. Anti-HER-2/neu antibody did not induce apoptosis in HER-2/neu negative HBL-100 and HTB-132 cell lines. Our results indicate that within the panel of tested breast cancer cell lines, anti-Her-2/neu antibody-induced apoptosis was independent from the presence of intact p53.
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PMID:Anti-Her-2/neu antibody induces apoptosis in Her-2/neu overexpressing breast cancer cells independently from p53 status. 1174

Muscle invasion is the usual presentation of schistosomal squamous cell carcinoma of the urinary bladder. It is unclear whether this invasive behavior is secondary to the aggressive nature of the disease or to delay in diagnosis. Fixed paraffin-embedded hematoxylin and eosin-stained sections of 15 cystectomy specimens from 15 patients (14 males, 1 female) (age range, 40 to 67 years), histologically confirmed as schistosomal squamous cell carcinoma, were assessed for grade (G1, n = 3; G2, n = 7; G3, n = 5) and pathological stage (PT category: PT2, n = 4; PT3a, n = 9; PT3b, n = 2). Immunostaining was performed for mutant p53, bcl-2, HER2/neu, and MIB-1 (proliferation), using steam antigen retrieval and an avidin-biotin complex method. Frequency of strong immunoreactivity was high for mutant p53 (73%) and MIB-1 (87% intermediate or high) but low for bcl-2 (20%) and HER2/neu (27%). There was no significant correlation of any of the four markers with either grade or stage. Hence, schistosomal bladder squamous cell carcinoma is felt to be an aggressive carcinoma de novo. The high frequency of mutant p53 expression (73%) and an intermediate to high proliferation index (87%) suggests this. The lack of correlation between histological grade and all four markers studied suggests that grading is not of prognostic value.
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PMID:Muscle invasive schistosomal squamous cell carcinoma of the urinary bladder: frequency and prognostic significance of p53, BCL-2, HER2/neu, and proliferation (MIB-1). 1534 22

Mechanisms involved in cellular radioresistance are mostly unknown and may be related to specific genetic alterations. In order to correlate the most frequent oncogenic alterations detected in tumors and ionizing radiation resistance, we studied the effect of irradiation on murine keratinocytes transformed by different oncogenes. Mouse PAM 212 keratinocytes were transformed by transfection or retroviral mediated infection with the oncogenes v-H-ras, v-myc, adenovirus Ela, neu and a mutant p53 (mp53). Cells were gamma irradiated with a Co-60 source. Cell viability was evaluated by the crystal violet method and thymidine uptake and data adjusted to the linear-quadratic model. Surviving fraction 2Gy (SF2) and DO was calculated. Cell cycle study was assessed by incorporation of bromodeoxyridine (BrdUrd) and flow cytometry. p53 protein was studied by Western-blot and apoptosis in DNA agarose gels. The surviving fraction for the different keratinocytes, PAM 212, 212 neo, 212 Ela, 212 v-H-ras, 212 myc, 212 neu and 212 mp53 was 0.79, 0.78, 0.34, 0.82, 0.68, 0.74, and 0.72, respectively. Ela oncogene induced a great sensitivity to irradiation and v-H-ras a mild radioresistance. In flow cytometry, 212 Ela keratinocytes displayed a pronounced and prolonged arrest in G2/M phase. Apoptosis was observed after irradiation only in the 212 Ela keratinocytes. With these results, we conclude that some oncogene products may modulate radiosensitivity in keratinocytes. Mechanisms involved in radiosensitivity mediated by the Ela oncogene seem to be related to p53 protein level, induction of apoptosis and to an irreversible premitotic arrest in G2/M phase, ineffective for repair of DNA damage.
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PMID:Oncogenes and cellular-sensitivity to radiotherapy - a study on murine keratinocytes transformed by v-h-ras, v-myc, v-Neu, adenovirus e1a and mutant p53. 2155 21