Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lung cancer is a worldwide problem. At the time of diagnosis, 50% of patients have advanced incurable disease. Different chemotherapy combinations--with or without targeted therapies--yield similar results despite the continuous efforts of clinicians. However, molecular biological studies have already shed a great deal of light on the existence of multiple genetic aberrations that can be useful for customizing treatment. mRNA transcripts involved in DNA repair pathways, such as ERCC1 and BRCA1, confer selective resistance to cisplatin or taxanes, whereas thioredoxin confers a broad spectrum of chemoresistance. Polymorphisms in DNA repair genes and methylation of checkpoint genes in circulating serum DNA could become important predictive markers of survival in certain cisplatin-based regimens. Epidermal growth factor receptor tyrosine kinase mutations are the crux of targeted therapies, whereas epithelial-mesenchymal transitions and HER3 mRNA levels are promising ancillary markers for treatment with epidermal growth factor receptor tyrosine kinase inhibitors.
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PMID:Predicting the outcome of chemotherapy for lung cancer. 1676 44

Alternative splicing is a crucial mechanism for generating protein diversity. Different splice variants of a given protein can display different and even antagonistic biological functions. Therefore, appropriate control of their synthesis is required to assure the complex orchestration of cellular processes within multicellular organisms. Mutations in cis-acting splicing elements or changes in the activity of constitutive or alternative splicing could have a profound regulatory proteins that compromise the accuracy of either impact on human pathogenesis, in particular in tumor development and progression. Mutations in splicing elements, for example, have been found in genes such as LKB1, KIT, CDH17, KLF6 and BRCA1, and changes in trans-acting regulators can affect the expression of genes such as Ron, RAC1 and CD44.
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PMID:The connection between splicing and cancer. 1678 44

Docetaxel has come into wide use recently for the treatment of breast cancer in neoadjuvant, adjuvant and metastatic settings. Docetaxel binds to beta-tubulin and causes kinetic abnormalities in the dynamics of microtubules by increasing their polymerization and inhibiting their depolymerization, resulting in elevated levels of microtubule formation. During metaphase, defective spindle formation induced by docetaxel activates the mitotic checkpoint and leads to cell cycle arrest, culminating in apoptosis. However, docetaxel is not effective for all breast cancers. For example, in metastatic settings, the response rate to docetaxel reportedly ranges from 30 to 50%. It is therefore very important to develop a diagnostic method with high accuracy for the prediction of sensitivity to docetaxel in order to avoid unnecessary treatment. Currently it is impossible to identify, before the initiation of therapy, the patients for whom docetaxel will be effective. Various biological parameters have been studied clinically for their ability to predict response to docetaxel, such as parameters related to: (1) efflux (p-glycoprotein) and metabolism (CYP3A4); (2) beta-tubulin (somatic mutation of beta-tubulin and changes in beta-tubulin isotypes levels); (3) cell cycle (HER2, BRCA1 and Aurora-A); and (4) apoptosis (p53, BCL2 and thioredoxin). More recently, gene expression profiling techniques have been used for the development of a prediction model for response to docetaxel. In the present paper, clinical studies that have been conducted recently to identify predictive factors for response to docetaxel are reviewed together with a presentation of our recent work in this field.
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PMID:Predictive factors for response to docetaxel in human breast cancers. 1680 18

As a clinical entity, breast cancer appears to be a series of subforms, each with a relatively specific molecular phenotype. Among the characteristics that differentiate these subforms are sex hormone receptor expression, HER2 expression, p53 mutation, high-grade histopathology, and particular gene expression array patterns. Sporadic basal-like breast cancer is one such form. It is a relatively common, high-grade, hormone receptor and HER2-expression-negative, p53 mutation-bearing tumor and is particularly lethal. Although wild type for BRCA1, it is a sporadic phenocopy of most cases of BRCA1(/) breast cancer. Not only do the cells of the two tumors resemble one another with respect to the above-noted characteristics, they also share a defect in the maintenance of an intact, inactive X chromosome (Xi). Other high-grade and most low-grade tumors are rarely defective at Xi. This evidence suggests that an Xi defect contributes to the evolution of both sporadic and BRCA1(/) basal-like breast tumors.
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PMID:Abnormalities of the inactive X chromosome are a common feature of BRCA1 mutant and sporadic basal-like breast cancer. 1686 42

HER4 expression in human breast cancers correlates with a positive prognosis. While heregulin inhibits the growth of HER4-positive breast cancer cells, it does so by undefined mechanisms. We demonstrate that heregulin-induced HER4 activity inhibits cell proliferation and delays G(2)/M progression of breast cancer cells. While investigating pathways of G(2)/M delay, we noted that heregulin increased the expression of BRCA1 in a HER4-dependent, HER2-independent manner. Induction of BRCA1 by HER4 occurred independently of the cell cycle. Moreover, BRCA1 expression was elevated in HER4-postive human breast cancer specimens. Heregulin stimulated c-Jun N-terminal kinase (JNK), and pharmacologic inhibition of JNK impaired heregulin-enhanced expression of BRCA1 and mitotic delay; inhibition of Erk1/2 did not. Knockdown of BRCA1 with small interfering RNA in a human breast cancer cell line interfered with HER4-mediated mitotic delay. Heregulin/HER4-dependent mitotic delay was examined further with an isogenic pair of mouse mammary epithelial cells (MECs) derived from mice harboring homozygous LoxP sites flanking exon 11 of BRCA1, such that one cell line expressed BRCA1 while the other cell line, after Cre-mediated excision, did not. BRCA1-positive MECs displayed heregulin-dependent mitotic delay; however, the isogenic BRCA1-negative MECs did not. These results suggest that heregulin-mediated growth inhibition in HER4-postive breast cancer cells requires BRCA1.
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PMID:Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1. 1691 27

There are currently only two predictive markers of response to chemotherapy for breast cancer in routine clinical use, namely the Estrogen receptor-alpha and the HER2 receptor. The breast and ovarian cancer susceptibility gene BRCA1 is an important genetic factor in hereditary breast and ovarian cancer and there is increasing evidence of an important role for BRCA1 in the sporadic forms of both cancer types. Our group and numerous others have shown in both preclinical and clinical studies that BRCA1 is an important determinant of chemotherapy responses in breast cancer. In this review we will outline the current understanding of the role of BRCA1 as a determinant of response to DNA damaging and microtubule damaging chemotherapy. We will then discuss how the known functions of this multifaceted protein may provide mechanistic explanations for its role in chemotherapy responses.
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PMID:BRCA1--a good predictive marker of drug sensitivity in breast cancer treatment? 1691 82

This review highlights the numerous molecular biology findings in the field of lung cancer with potential therapeutic impact in both the near and distant future. At least six lines of research have recently emerged as potential contributors to changes in clinical practice. Abundant pre-clinical and clinical data indicate that BRCA1 mRNA expression is a differential modulator of chemotherapy sensitivity. Low levels predict cisplatin sensitivity and antimicrotubule drug resistance, and the opposite occurs with high levels. Secondly, single nucleotide polymorphisms in the ERCC1 gene influence survival and toxicity with cisplatin-based chemotherapy. The main core of recent research has centered on EGFR mutations and gene copy numbers. For the first time, EGFR mutations have been shown to predict dramatic responses in metastatic lung adenocarcinomas, with a threefold increase in time to progression and survival in patients receiving EGFR tyrosine kinase inhibitors. In contrast, K-ras mutations confer a negative effect in these patients. Evidence has also been accumulated on the crosstalk between estrogen and EGFR receptor pathways, paving the way for clinical trials of EGFR tyrosine kinase inhibitors plus aromatase inhibitors. microRNAs control the expression of cognate target genes, and downregulation of Dicer has been shown to be a strong predictor of relapse in surgically resected non-small-cell lung cancer patients. Finally, overexpression of the Wingless-type (Wnt) genes and methylation of Wnt antagonists like WIF and secreted frizzled related proteins have been documented in non-small-cell lung cancer and are believed to be an important mechanism of cancer stem cell maintenance.
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PMID:Usefulness of predictive tests for cancer treatment. 1693 74

Analysis of the combined effects of polymorphisms in genes encoding xenobiotic metabolizing enzymes (XMEs) and DNA repair proteins may be a key to understanding the role of these genes in the susceptibility of individuals to mutagens. In the present study, we performed an in vitro experiment on lymphocytes from 118 healthy donors that measured the frequency of diepoxybutane (DEB) induced sister chromatid exchanges (SCEs) in relation to genetic polymorphisms in genes coding for XMEs (CYP1A1, CYP2E1, GSTT1, EPHX, and NAT2), as well as DNA repair proteins (XRCC1, XRCC2, XRCC3, XPD, XPA, XPC, XPG, XPF, ERCC1, BRCA1, NBS1, and RAD51). We found that GSTT1(-) and CYP2E1 c1/c2 polymorphisms were associated with higher DEB-induced SCE frequencies, and that NAT2 G(590)A was associated with lower SCE induction by DEB. Analysis of the effect of pairs of genes showed that for a fixed GSTT1 genotype, the SCE level increased with an increasing number of Tyr alleles in EPHX codon 113. We found that among GSTT1(+) individuals the DEB-induced SCE level was significantly lower when the EPHX 139 codon was His/Arg rather than His/His. An interaction between polymorphisms in CYP2E1 and at EPHX codon 113 was also observed. The results of our study confirm observations in cancer patients and in people exposed to xenobiotics indicating that sensitivity to mutagens depends upon a combined effect of a variety of "minor impact" genes. Moreover, our results indicate that polymorphisms in genes coding for XMEs have a greater influence on the genotoxic activity of DEB, measured by DEB-induced SCE frequency, than polymorphisms in genes encoding DNA repair proteins.
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PMID:Influence of polymorphisms in xenobiotic-metabolizing genes and DNA-repair genes on diepoxybutane-induced SCE frequency. 1707 1

A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain. To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry. We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors. We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.
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PMID:BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays. 1719 28

Breast cancers arising in carriers of germline BRCA1 mutations frequently have a basal-like phenotype. Basal-like cancers are characterized by high histological grade, central necrotic areas, foci with metaplastic differentiation, lack of hormone receptor and HER2 (ErbB2) expression, and consistent positivity for basal markers, including CK5/6, CK14, and EGFR. We have used germline manipulation to generate a conditional mouse model of Brca1 deficiency. Transgenic expression of Cre recombinase in the mammary gland of these mice results in deletion of exons encoding the C-terminus of Brca1 and leads to tumour formation when combined with heterozygosity for a p53 mutation. Histologically, these mammary gland tumours were characterized by high histological grade, central necrotic areas, and presence of homologous metaplastic elements. These metaplastic elements consisted of neoplastic spindle cells or squamous cell differentiation in the form of keratin pearls or individual cell keratinization. Immunohistochemical analysis revealed expression of basal-like markers in all cases. The tumour phenotype generated in our mouse model was compared with published data on human basal-like breast carcinomas and also with metaplastic breast cancers with a basal-like phenotype; the comparison showed that we have generated a mouse model of basal-like breast cancer, which should prove useful in testing new and targeted treatments for this type of breast cancer.
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PMID:A mouse model of basal-like breast carcinoma with metaplastic elements. 1721 42


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