Browsing by Subject "BRCA1"

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    Germline mutations in the BRCA1 and BRCA2 genes in Turkish breast ovarian cancer patients
    (John Wiley & Sons, Inc., 2003) Manguoglu, A. E.; Lüleci, G.; Özçelik, T.; Çolak, T.; Schayek, H.; Akaydin, M.; Friedman, E.
    In this study we genotyped Turkish breast/ovarian cancer patients for BRCA1/BRCA2 mutations: protein truncation test (PTT) for exon 11 BRCA1 of and, multiplex PCR and denaturing gradient gel electrophoresis (DGGE) for BRCA2, complemented by DNA sequencing. In addition, a modified restriction assay was used for analysis of the predominant Jewish mutations: 185delAG, 5382InsC, Tyr978X (BRCA1) and 6174delT (BRCA2). Eighty three breast/ovarian cancer patients were screened: twenty three had a positive family history of breast/ovarian cancer, ten were males with breast cancer at any age, in eighteen the disease was diagnosed under 40 years of age, one patient had ovarian cancer in addition to breast cancer and one patient had ovarian cancer. All the rest (n=30) were considered sporadic breast cancer cases. Overall, 3 pathogenic mutations (3/53‐5.7%) were detected, all in high risk individuals (3/23–13%): a novel (2990insA) and a previously described mutation (R1203X) in BRCA1, and a novel mutation (9255delT) in BRCA2. In addition, three missense mutations [two novel (T42S, N2742S) and a previously published one (S384F)] and two neutral polymorphisms (P9P, P2532P) were detected in BRCA2. Notably none of the male breast cancer patients harbored any mutation, and none of the tested individuals carried any of the Jewish mutations. Our findings suggest that there are no predominant mutations within exon 11 of the BRCA1 and in BRCA2 gene in Turkish high risk families.
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    Identification of genes induced by BRCA1 in breast cancer cells
    (Academic press, 2002) Atalay, A.; Crook, T.; Ozturk, M.; Yulug, I. G.
    Inherited mutations of the BRCA1 gene predispose to breast, ovarian, and other cancers. The role of the BRCA1 gene in the maintenance of chromosomal integrity is linked to a number of biological properties of its protein product, including transcriptional regulation. In the present study, we have used suppression subtractive hybridisation (SSH) to identify genes induced by BRCA1 by comparing control MCF7 breast carcinoma cells (driver) with MCF7 cells ectopically expressing BRCA1 (tester) and generated a forward subtracted cDNA library. We screened 500 putative positive clones from this library. Two hundred and ten of these clones were positive by differential screening with forward and reverse subtracted probes and the 65 cDNA clones which showed more than fivefold increase were selected for sequencing analysis. We clustered 46 different genes that share high homology with sequences in the GenBank/EMBL databases. Among these, 30 were genes whose function had been previously identified while the remaining 16 clones were genes with unknown functions. Of particular interest, BRCA1 gene induces the expression of genes encoding DNA repair proteins RAD21 and MSH2, ERBB2/HER2 interacting protein ERBIN, meningioma-associated protein MAC30, and a candidate ovarian tumour-suppressor OVCA1. Northern and Western blot analyses confirmed that the expression of these five genes are up-regulated following BRCA1 overexpression in MCF7 and UBR60-bcl2 cells. This is the first study reporting a set of BRCA1-induced genes in breast carcinoma cells by the SSH technique. We suggest that some known genes identified in this study may provide new insights into the tumour-suppressor function of BRCA1. © 2002 Elsevier Science (USA). All rights reserved.
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    p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1-and BRCA2-associated breast tumours
    (Nature Publishing Group, 1998) Crook, T.; Brooks, L. A.; Crossland, S.; Osin, P.; Barker, K. T.; Waller, J.; Philp, E.; Smith, P. D.; Yulug, I.; Peto, J.; Parker, G.; Allday, M. J.; Crompton, M. R.; Gusterson, B. A.
    The status of p53 was investigated in breast tumours arising in germ-line carriers of mutant alleles of BRCA1 and BRCA2 and in a control series of sporadic breast tumours. p53 expression was detected in 20/26 (77%) BRCA1-, 10/22 (45%) BRCA2-associated and 25/72 (35%) grade-matched sporadic tumours. Analysis of p53 sequence revealed that the gene was mutant in 33/50 (66%) BRCA-associated tumours, whereas 7/20 (35%) sporadic grade-matched tumours contained p53 mutation (P < 0.05). A number of the mutations detected in the BRCA-associated tumours have not been previously described in human cancer databases, whilst others occur extremely rarely. Analysis of additional genes, p16(INK4), Ki-ras and β-globin revealed absence or very low incidence of mutations, suggesting that the higher frequency of p53 mutation in the BRCA-associated tumours does not reflect a generalized increase in susceptibility to the acquisition of somatic mutation. Furthermore, absence of frameshift mutations in the polypurine tracts present in the coding sequence of the TGF β type II receptor (TGF β IIR) and Bax implies that loss of function of BRCA1 or BRCA2 does not confer a mutator phenotype such as that found in tumours with microsatellite instability (MSI). p21(Waf1) was expressed in BRCA-associated tumours regardless of p53 status and, furthermore, some tumours expressing wild-type p53 did not express detectable p21(Waf1). These data do not support, therefore, the simple model based on studies of BRCA-/- embryos, in which mutation of p53 in BRCA-associated tumours results in loss of p21(Waf1) expression and deregulated proliferation. Rather, they imply that proliferation of such tumours will be subject to multiple mechanisms of growth regulation.
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    Targeting mirna-protein regulatory networks to enhance chemotherapy response in BRCA1-mutated TNBCs
    (2016-09) Eyüpoğlu, Erol
    Breast cancer is the second most common cancer and the leading cause of cancer associated deaths in women worldwide. Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. BRCA1-mutated TNBC patients generally respond well to DNA cross-linking agents like Cisplatin. However, most of the patients acquire resistance and eventually die. Therefore, there is a dire need of developing promising approaches to enhance chemo-response, hence, extending the survival of TNBC patients. MicroRNAs (miRNAs) play active role in controlling proliferation, apoptosis, invasion and drug resistance in cancer. However, the role of miRNA-protein interactions as a regulatory network in determining chemotherapy response of TNBCs has not been elucidated yet. Thus, we aimed to delineate miRNAs and miRNA-protein regulatory networks controlling chemotherapy resistance/response in BRCA1–mutated TNBCs. We firstly confirmed that BRCA1-mutated breast cancer cells are more sensitive to Cisplatin as compared to BRCA1-competent cells. Afterwards, developing acquired chemotherapy resistant cell line model and using next generation sequencing technology (both miR-Seq and RNA-Seq), we have unravelled that p53 signalling is the upstream regulator of Cisplatin resistance. Moreover, with the use of Ingenuity Pathway Anlaysis (IPA) which uses omics data from a variety of experimental platforms, we analyzed, combined and modelled miRNA-mRNA interactions regulating Cisplatin resistance for the first time in a network manner. Interestingly, we identifed several network motifs e.g. coherent and incoherent feedforward loops centered around p53 protein which need further experimental validations. Again for the first time, this study has reported the re-sensitization effect of miR-455 family on Cisplatin resistance in breast cancer. Overall, findings of this study might be used as an alternative strategy for treatment of BRCA1-mutated TNBCs by modulating miRNAs and their targets to re-sensitize Cisplatin resistant tumors.
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    TP53 mutations in familial breast cancer: Functional aspects
    (John Wiley & Sons, Inc., 2003) Gasco, M.; Yulug, I. G.; Crook, T.
    Mutation in p53 (TP53) remains one of the most commonly described genetic events in human neoplasia. The occurrence of mutations is somewhat less common in sporadic breast carcinomas than in other cancers, with an overall frequency of about 20%. There is, however, evidence that p53 is mutated at a significantly higher frequency in breast carcinomas arising in carriers of germ-line BRCA1 and BRCA2 mutations. Some of the p53 mutants identified in BRCA1 and BRCA2 mutation carriers are either previously undescribed or infrequently reported in sporadic human cancers. Functional characterization of such mutants in various systems has revealed that they frequently possess properties not commonly associated with those occurring in sporadic cases: they retain apoptosis-inducing, transactivating, and growth-inhibitory activities similar to the wild-type protein, yet are compromised for transformation suppression and also possess an independent transforming phenotype. The occurrence of such mutants in familial breast cancer implies the operation of distinct selective pressures during tumorigenesis in BRCA-associated breast cancers.