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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The etiology of breast cancer involves a complex interplay of various factors, including genetic alterations. Many studies have been devoted to the identification and characterization of mutations that occur frequently during breast tumorigenesis. The major types of genetic abnormalities that are frequently observed in breast tumors are amplification of protooncogenes (MYC, ERBB2) and DNA from chromosome band 11q13; mutation of TP53; and loss of heterozygosity from chromosomes and chromosome arms 1, 3p, 6q, 7q, 8p, 11, 13q, 16q, 17, 18q, and 22q. The latter may correspond to losses or inactivations of tumor suppressor genes. Recently, linkage analyses of large families with a predisposition to breast cancer have been performed in order to map breast cancer susceptibility genes (TP53, BRCA1, BRCA2). The findings have thrown light on the molecular mechanisms of breast cancer and have enabled various genetic markers to be used in clinical oncology.
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PMID:Genetic alterations in breast cancer. 860 12

Allelic deletions on chromosome 17q21 in sporadic ovarian cancer are common, suggesting that inactivation of a tumor suppressor gene(s) in that region may be important for the etiology of these tumors. The recently identified BRCA1 gene on 17q21, involved in the development of familial breast/ovarian cancer, could be a candidate. However, inactivating mutations on BRCA1 in sporadic ovarian cancer has been rarely described. Furthermore, the potential relationship of BRCA1 gene to ovarian tumors of borderline malignancy remains also unclear. We constructed a highly detailed deletion map of chromosome 17q21 based on PCR amplification of eight polymorphic tandem repeat markers in a 650 kb area including three BRCA1 intragenic markers. DNA from 52 sporadic ovarian cancers and 26 borderline tumors, together with their corresponding normal control tissues were used. Only one borderline tumor showed loss of heterozygosity at one marker, whereas 65% of invasive ovarian cancers displayed allelic loss in at least one of the markers studied. A common deletion unit, located approximately 60kb centromeric to BRCA1, was revealed. These results suggest that inactivation of the BRCA1 gene may not be responsible for the development of borderline ovarian tumors and that another tumor suppressor gene, located centromeric to the BRCA1 gene, may play a role in sporadic ovarian cancer development.
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PMID:A 400 kb novel deletion unit centromeric to the BRCA1 gene in sporadic epithelial ovarian cancer. 863 95

Using primer extension and 5' RACE, we have mapped the 5' end of the BRCA1 gene and identified a new 5' exon. Two distinct BRCA1 transcripts differing by the first exons were found; these transcripts were generated by the alternative use of dual promoters and alternative splicing. The expression of the distinct transcripts was examined in four primary tissues (placenta, mammary gland, testis and thymus), six normal or cancer cell lines, four primary breast tumor tissues and four primary ovary tumour tissues. Both transcripts were detected in all the samples studied, with the exon 1a transcript being the major expressed form in mammary gland and the exon 1b transcript in placenta. This suggests that the two transcripts may be expressed in a tissue-specific fashion. The 5' flanking regions of both BRCA1 transcripts were analysed, neither contains a TATA box. Initiator elements, which have been proposed to mediate transcription in TATA-less promoters, were found at the transcription initiation sites. Transcription factor binding sites such as Sp1, PEA3, C/EBP, CREB, E4F1 and Pu boxes were identified in the 5' flanking regions of the exon 1a transcript, and Sp1, NF-kB and PEA3 binding sites in the 5' flanking region of the exon 1b transcript. The interactions of these DNA elements with trans-acting factors are likely to modulate the alternative use of the distinct transcription start sites and the expression of the BRCA1 gene.
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PMID:Distinct transcription start sites generate two forms of BRCA1 mRNA. 863 96

Recently, BRCA1, a familial breast and ovarian cancer susceptible gene has been cloned and shown to be either lost or mutated in families with breast and ovarian cancers. BRCA1 has been postulated to encode a tumor suppressor, a protein that acts as a negative regulator of tumor growth. We have characterized the BRCA1 gene products by Western blot and immunoprecipitation analysis in mouse and tumor cells. Multiple BRCA1 polypeptides of approximately 225, 185, 160, 145, 100, 52 and 38 kD were identified in these cells. BRCA1 proteins were found to be localized mainly in the nucleus of normal Rat1 cells and human breast cancer cells. In order to understand the role of BRCA1 in cell transformation, we have established a stable NIH3T3 cell line expressing BRCA1 antisense RNA. The inhibition of expression of endogenous BRCA1 protein was detected in NIH3T3 transfectants by Western blot analysis. The antisense BRCA1 expressing NIH3T3 cells showed accelerated growth rate, anchorage independent growth and tumorigenicity in nude mice unlike the parental and sense transfectants. These results provide the first direct biological evidence for the possible function of BRCA1 as a tumor suppressor gene.
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PMID:Antisense RNA to the putative tumor suppressor gene BRCA1 transforms mouse fibroblasts. 863 8

Nine different germ-line mutations in the BRCA1 breast and ovarian cancer susceptibility gene were identified in 15 of 47 kindreds from southern Sweden, by use of SSCP and heteroduplex analysis of all exons and flanking intron region and by a protein-truncation test for exon 11, followed by direct sequencing. All but one of the mutations are predicted to give rise to premature translation termination and include seven frameshift insertions or deletions, a nonsense mutation, and a splice acceptor site mutation. The remaining mutation is a missense mutation (Cys61Gly) in the zinc-binding motif. Four novel Swedish founding mutations were identified: the nucleotide 2595 deletion A was found in five families, the C 1806 T nonsense mutation in three families, the 3166 insertion TGAGA in three families, and the nucleotide 1201 deletion 11 in two families. Analysis of the intragenic polymorphism D17S855 supports common origins of the mutations. Eleven of the 15 kindreds manifesting BRCA1 mutations were breast-ovarian cancer families, several of them with a predominant ovarian cancer phenotype. The set of 32 families in which no BRCA1 alterations were detected included 1 breast-ovarian cancer kindred manifesting clear linkage to the BRCA1 region and loss of the wild-type chromosome in associated tumors. Other tumor types found in BRCA1 mutation/haplotype carriers included prostatic, pancreas, skin, and lung cancer, a malignant melanoma, an oligodendroglioma, and a carcinosarcoma. In all, 12 of 16 kindreds manifesting BRCA1 mutation or linkage contained ovarian cancer, as compared with only 6 of the remaining 31 families (P<.001). The present study confirms the involvement of BRCA1 in disease predisposition for a subset of hereditary breast cancer families often characterized by ovarian cancers.
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PMID:Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden. 864 2

The recent remarkable progress in molecular biology has revealed that various kinds of genetic alteration occur in cancers. Recently, many genes that cause hereditary cancer have been identified. For example, hMSH2 and hMLH1, which are known as DNA mismatch repair genes have been found to cause HNPCC (hereditary non-poliposis colorectal cancer). Mutation of RET oncogene has been recognized in the families of MEN (multiple endocrine neoplasia) type II. Mutations of the tumor suppressor genes are the most common changes in the genes of familial cancer. BRCA1 and BRCA2 are tumor suppressor genes that have recently been identified as familial breast and ovarian cancer, familial breast cancer genes. This paper reviewed the hereditary cancer families in which genetic alterations have been revealed and the recent progress in mapping and cloning of familial breast cancer candidate genes which have not been identified.
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PMID:[Familial cancer and oncogenic factors]. 867 87

The usefulness of prognostic factors in gynecological cancer was evaluated using the oncogenes, tumor suppressor genes and DNA viruses detected with the molecular biological technique. In uterine cervical cancer, HPV types 16 and 18 are considered to have a high oncogenic risk, and are commonly associated with high grade CIN and invasive cancer under persistent HPV infection. C-myc overexpression in advanced stage and p53 mutation in HPV negative case are associated with poor survival. In endometrial cancer, oncogene activation and expression are less frequent than in cervical and ovarian cancer. K-ras point mutation (codon 12) tumors are more aggressive and c-erbB-2 overexpression are associated with metastasis and poor survival. In ovarian cancer, there are numerous abnormalities of oncogenes and tumor suppressor genes. Especially, EGF-R and PDGF-R alpha expression are associated with decreased survival. p53 mutation also decreases survival and response to chemotherapy. Recently. MSH2 (Lynch II syndrome) and BRCA1 gene are known to relate with familial ovarian cancer.
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PMID:[Evaluation of prognostic factors in gynecological cancer examined by molecular biological study]. 868 14

BRCA1 is proposed to be a tumor suppressor gene. To explore the biological function of BRCA1, a partial deletion (amino acids 300-361) of mouse Brca1 exon 11 was introduced into the genome of embryonic stem (ES) cells by homologous recombination. Mice carrying one mutated allele of Brca1 appear normal and are fertile up to 10 months of age without any sign of illness. However, no viable progeny homozygous for the Brca1 mutant allele were obtained. Detailed analysis of large numbers of embryos at different stages of development indicated that the homozygous mutant concepti are severely retarded in growth as early as embryonic day 4.5 (E4.5) and are resorbed completely by E8.5. Although the homozygotes at E5.5-E6.5 are able to synthesize DNA and display distinguishable embryonic and extraembryonic structures, they fail to differentiate and form egg cylinders. Consequently, they were unable to form primitive streaks and undergo gastrulation. Consistent with these in vivo results, blastocysts homozygous for mutated Brca1 alleles are at a considerable disadvantage when grown in vitro. These observations suggest that Brca1 has an important role in the early development of mouse embryos.
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PMID:Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development. 869 42

The breast and ovarian cancer susceptibility gene BRCA1, is a nuclear phosphoprotein which functions as a tumor suppressor. To investigate the role of BRCA1 in apoptosis, we have developed mouse fibroblast cell lines and human breast cancer cell lines expressing BRCA1. The expression of BRCA1 protein in the BRCA1 transfectants were analysed by immunofluorescence and immunohistochemistry. The BRCA1 transfectants showed a flattened morphology compared to the parental cells. We show that serum deprivation or calcium ionophore treatment of BRCA1 transfectants resulted in programmed cell death. These results indicate that BRCA1 genes may play a critical role in the regulation of apoptosis. Thus, since a wide variety of human malignancies like breast and ovarian cancers have a decreased ability to undergo apoptosis, this could be due to lack/decreased levels of functional BRCA1 proteins. Treatments that are aimed at increasing the apoptotic threshold by BRCA1 gene therapy may have the potential to prevent the progression of these malignancies.
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PMID:Induction of apoptosis by the tumor suppressor protein BRCA1. 870 May 35

The breast and ovarian cancer susceptibility gene BRCA2 has recently been isolated. A role for BRCA2 in sporadic breast and ovarian cancer has been suggested by loss of heterozygosity (LOH) studies which show frequent LOH in the BRCA2 region at chromosome 13q12. In addition, the observation of nonrandom loss of the wild-type chromosome in a breast/ovarian cancer family which shows linkage to BRCA2 suggests it may act as a tumor suppressor gene. To determine the extent of somatic alteration involving BRCA2 in sporadic ovarian cancer, 50 tumors were analyzed for mutations throughout the entire BRCA2 coding region. Mutations predicted to result in truncation of the BRCA2 protein were detected in four tumors. Analysis of germline DNA revealed two of these alterations to be of somatic origin. In addition, all four tumors exhibited loss of the second BRCA2 allele as predicted by Knudson's hypothesis for a tumor suppressor gene. These results suggest that, as is the case with BRCA1, somatic mutations of BRCA2 are infrequent in sporadic ovarian cancer, despite the relatively high frequency of LOH detected around the BRCA2 locus.
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PMID:Somatic and germline mutations of the BRCA2 gene in sporadic ovarian cancer. 870 94


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