Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It could be demonstrated that plasma and tissue fibronectin (FN) increase with age. Some age dependent diseases as diabetes, osteoarthritis and Werner syndrome produce also an increase of tissue fibronectin biosynthesis. Plasma fibronectin decreases in diabetes and in breast cancer. Alternative splicing of the FN gene appears also to vary with age and in some related pathologies. Nutritional status and UV light also influence FN biosynthesis. It appears therefore that the determination of plasma FN and its isoforms as well as the study of tissue FN may be of interest for the study of chronological aging and related pathologies.
 ...
PMID:[Fibronectin, aging and related pathologies]. 183 21

Detailed physical maps of the human genome are important resources for the identification and isolation of disease genes and for studying the structure and function of the genome. To improve the definition of the 8p12-p21 chromosomal region, an integrated physical and genetic map was constructed extending from the genes. NEFL to FGFR1. The map comprises a series of contigs (the larger of these being around 9 Mb) of yeast artificial chromosomes (YACs) spanning the proximal region of deletion involved in a broad range of human cancers, including breast carcinomas, and in the Werner syndrome. In addition, losses of heterozygosity at 8p markers and linkage analysis of breast cancer families were also detailed. Finally, several genes potentially involved in 8p-associated diseases, namely GTF2E2, PPP2CB, and HGL, were precisely mapped within the YAC contigs. The reported map and contigs of YACs should facilitate the search for putative genes involved in sporadic and familial breast cancer as well as in the Werner syndrome.
 ...
PMID:Integrated map of the chromosome 8p12-p21 region, a region involved in human cancers and Werner syndrome. 878 18

A yeast artificial chromosome (YAC), P1, and cosmid clone contig was constructed for the Werner syndrome (WRN) region of chromosome 8p12-p21 and used to clone a candidate gene for WRN. This region also possibly contains a familial breast cancer locus. The contig was initiated by isolating YACs for the glutathione reductase (GSR) gene and extended in either direction by walking techniques. Sequence-tagged site (STS) markers were generated from subclones of 2 GSR YACs and used to identify P1 and cosmid clones. Additional STSs were generated from P1 and cosmid clones and from potential expressed sequences identified by cDNA selection and exon amplification methods. The final contig was assembled by typing 17 YACs, 20 P1 clones, and 109 cosmids for 54 STS markers. The WRN region could be spanned by 2 nonchimeric YACs covering approximately 1.4 Mb. A P1/cosmid contig was established covering the core 700-800 kb of the WRN region. Fifteen new short tandem repeat polymorphisms and 2 biallelic polymorphic markers were identified and included as STSs in the contig. Analysis of these markers in Werner syndrome subjects demonstrates that the candidate WRN gene is in a region of linkage disequilibrium.
 ...
PMID:A YAC, P1, and cosmid contig and 17 new polymorphic markers for the Werner syndrome region at 8p12-p21. 881 76

Breast cancer is considered to display a high degree of intratumor heterogeneity, without any obvious morphological and pathological steps to define sequential evolution, and its progression may vary among individual tumors. In an attempt to elucidate these etiological and phenotypic complexities, the present study, based on the fundamental concept that genomic instability is the engine of both tumor progression and tumor heterogeneity, was conducted to test the hypothesis that breast cancer pathogenesis is driven by double-strand break (DSB)-initiated chromosome instability (CIN). The rationale underlying this hypothesis is derived from the clues provided by family breast cancer syndromes, in which susceptibility genes, including p53, ATM, BRCA1 and BRCA2, are involved within the common functional pathway of DSB-related checkpoint/ repair. Because genomic deletion caused by DSB is reflected in the genetic mechanism of loss of heterozygosity (LOH), this genome-wide LOH study was conducted, using 100 tumors and 400 microsatellite markers. To minimize the effect of heterogeneity within tumors, the experimental technique of laser capture microdissection was used to ensure that genetic and phenotypic examinations were based on the same tumor cells. Support for our hypothesis comes from the observations that: (a) the extent of DSB-initiated CIN in tumors significantly increased as tumors progressed to poorer grades or later stages; (b) in the sequential steps toward CIN, the loci of p53 and ATM, the key checkpoint genes against DSB, were lost at the earliest stage; and (c) many loci identified to be important in breast tumorigenesis were the genomic sites possibly harboring the genes involved in DSB-related checkpoint/repair (including RAD51, RAD52, and BRCA1) or CIN (including FA-A, FA-D, and WRN), and a higher number of these loci showing LOH was significantly associated with increased level of DSB-initiated CIN (P < 0.0001). Breast cancers are thus considered to be sequentially progressive with CIN. However, CIN might also cause genetic heterogeneity, which was revealed by the findings that LOH at some markers was observed only in the component of ductal carcinoma in situ but not in the invasive component of the same tumors. In addition, some markers were found to preferentially lose at specific tumor grades, implying their contribution to genetic heterogeneity during tumor development. Therefore, this study suggests that breast cancer progression is clonal with regard to CIN, but different breast cancers would present distinct molecular profiles resulting from genetic heterogeneity caused by CIN.
 ...
PMID:Genome-wide search for loss of heterozygosity using laser capture microdissected tissue of breast carcinoma: an implication for mutator phenotype and breast cancer pathogenesis. 1091 64

Recent theories propose that a Western lifestyle may increase cancer risk through alterations in the metabolism of insulin and insulin-like growth factors (IGF: McKeown-Eyssen, 1994; Giovannucci, 1995; Kaaks, 19%; Werner & LeRoith, 1996). Insulin regulates energy metabolism, and increases the bioactivity of IGF-I, by enhancing its synthesis. and by decreasing several of its binding proteins (IGFBP; IGFBP-1 and -2). Insulin and IGF-I both stimulate anabolic processes as a function of available energy and elementary substrates (e.g. amino acids). The anabolic signals by insulin or IGF-I can promote tumour development by inhibiting apoptosis, and by stimulating cell proliferation. Furthermore, both insulin and IGF-I stimulate the synthesis of sex steroids, and inhibit the synthesis of sex hormone-binding globulin (SFIBG), a binding protein that regulates the bioavailability of circulating sex steroids to tissues. The present paper reviews epidemiological findings relating the risk of cancers of the colo-rectum, pancreas, breast, endometrium and prostate to body size (obesity, height) and physical activity, and discusses the relationships between obesity and physical activity and plasma levels of insulin, IGF-I and IGFBP. Subsequent sections review epidemiological findings relating cancer risk to indices of chronic hyperinsulinaemia, and to plasma levels of IGF-I and IGFBP. Conclusions are that chronic hyperinsulinaemia may be a cause of cancers of the colon, pancreas and endometrium, and also possibly of the breast. On the other hand, elevated plasma IGF-I, as total concentrations or relative to levels of IGFBP-3, appears to be related to an increased risk of prostate cancer, breast cancer in young women, and possibly cob-rectal cancer. For cancers of the endometrium, breast and prostate, these findings are discussed in the context of relationships between insulin and IGF-I and levels of bioavailable sex steroids.
 ...
PMID:Energy balance and cancer: the role of insulin and insulin-like growth factor-I. 1131 Apr 28

Chromosomal instability can occur when the DNA damage response and repair process fails, resulting in syndromes characterized by growth abnormalities, hematopoietic defects, mutagen sensitivity, and cancer predisposition. Mutations in ATM, NBS1, MRE11, BLM, WRN, and FANCD2 are responsible for ataxia telangiectasia (AT), Nijmegen breakage syndrome, AT-like disorder, Bloom and Werner syndrome, and Fanconi anemia group D2, respectively. This diverse group of disorders is thought to be linked through protein interactions with the breast cancer tumor susceptibility gene product, BRCA1. BRCA1 forms a multi-subunit protein complex referred to as the BRCA1-associated genome surveillance complex (BASC), which includes DNA damage repair proteins such as MSH2-MSH6 and MLH1, as well as ATM, NBS1, MRE11, and BLM. Although still controversial, this finding suggests similarities in the pathogenesis of the human chromosome breakage syndromes and a complementary role for each protein in DNA structure surveillance or damage repair.
 ...
PMID:Chromosomal breakage syndromes and the BRCA1 genome surveillance complex. 1173 19

Cancers arise as a result of genetic changes that impact upon cell proliferation through promoting cell division and/or inhibiting cell death. Tumour suppressor (TS) genes are the targets for many of these genetic changes. In general, both alleles of TS genes must be disrupted to observe a phenotypic effect. Broadly speaking, there are two types of TS gene: 'gatekeepers' and 'caretakers'. In contrast to gatekeepers, caretaker genes do not directly regulate proliferation, but act to prevent genomic instability. Thus, mutation of caretaker genes leads to accelerated conversion of a normal cell to a neoplastic cell. Many caretaker genes are required for the maintenance of genome integrity. This review focuses on those caretaker genes that play a role, directly or indirectly, in the repair of DNA strand breaks by the homologous recombination pathway, and that are associated with cancer-prone clinical syndromes, in particular ataxia telangiectasia, hereditary breast cancer, Bloom's syndrome and Werner's syndrome.
 ...
PMID:Caretaker tumour suppressor genes that defend genome integrity. 1192 76

We review the genes and proteins related to the homologous recombinational repair (HRR) pathway that are implicated in cancer through either genetic disorders that predispose to cancer through chromosome instability or the occurrence of somatic mutations that contribute to carcinogenesis. Ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), and an ataxia-like disorder (ATLD), are chromosome instability disorders that are defective in the ataxia telangiectasia mutated (ATM), NBS, and Mre11 genes, respectively. These genes are critical in maintaining cellular resistance to ionizing radiation (IR), which kills largely by the production of double-strand breaks (DSBs). Bloom syndrome involves a defect in the BLM helicase, which seems to play a role in restarting DNA replication forks that are blocked at lesions, thereby promoting chromosome stability. The Werner syndrome gene (WRN) helicase, another member of the RecQ family like BLM, has very recently been found to help mediate homologous recombination. Fanconi anemia (FA) is a genetically complex chromosomal instability disorder involving seven or more genes, one of which is BRCA2. FA may be at least partially caused by the aberrant production of reactive oxidative species. The breast cancer-associated BRCA1 and BRCA2 proteins are strongly implicated in HRR; BRCA2 associates with Rad51 and appears to regulate its activity. We discuss in detail the phenotypes of the various mutant cell lines and the signaling pathways mediated by the ATM kinase. ATM's phosphorylation targets can be grouped into oxidative stress-mediated transcriptional changes, cell cycle checkpoints, and recombinational repair. We present the DNA damage response pathways by using the DSB as the prototype lesion, whose incorrect repair can initiate and augment karyotypic abnormalities.
 ...
PMID:Recombinational DNA repair and human disease. 1242 31

Mutations of the human RecQ helicase genes WRN and BLM lead to rare autosomal recessive disorders, Werner and Bloom syndromes, which are associated with premature ageing and cancer predisposition. We tested the hypothesis whether three polymorphic, non-conservative amino acid exchanges in WRN and BLM act as low-penetrance familial breast cancer risk factors. Moreover, we examined the putative impact of p53 MspI 1798G>A, which is completely linked to p53PIN3, a 16 bp insertion/duplication that has been associated with reduced p53 expression, on familial breast cancer risk. Genotyping analyses, performed on 816 BRCA1/2 mutation-negative German familial breast cancer patients and 1012 German controls, revealed a significant association of the WRN Cys1367Arg polymorphism with familial breast cancer (OR = 1.28, 95% CI 1.06-1.54) and high-risk familial breast cancer (OR = 1.32, 95% CI 1.06-1.65). The analysis of p53 MspI 1798G>A, which is completely linked to p53PIN3, showed a significantly increased familial breast cancer risk for carriers of the 16 bp insertion/duplication, following a recessive mode (OR = 2.15, 95% CI = 1.12-4.11). WRN Cys1367Arg, located in the C-terminus, the binding site of p53, is predicted to be damaging. The joint effect of WRN Cys1367Arg and p53 MspI resulted in an increased breast cancer risk compared to the single polymorphisms (OR = 3.39, 95% CI 1.19-9.71). In conclusion, our study indicates the importance of inherited variants in the WRN and p53 genes for familial breast cancer susceptibility.
 ...
PMID:Interaction of Werner and Bloom syndrome genes with p53 in familial breast cancer. 1650 Dec 49

The high risk of developing cancer seen in human genetic diseases that resemble accelerated aging provides support for a tumorigenic contribution of the mechanisms and genes responsible for regulating life span and aging. We therefore speculated that the WRN gene (encoding RECQL2, a DNA helicase), the germline mutation of which causes the progeroid disorder Werner syndrome, may be associated with breast tumorigenesis. This hypothesis was tested in this case-control study of 935 primary breast cancer patients and 1,545 healthy controls by examining single-nucleotide polymorphisms (SNPs) in WRN. We were also interested in knowing whether any identified association between WRN and breast cancer was modified by reproductive risk factors reflecting susceptibility to estrogen exposure. Our hypothesis is that because estrogen is known to promote breast cancer development via its mitogenic effect leading to cell proliferation, and because WRN is an essential gene, as its suboptimal function leads to a severe decrease in proliferation, estrogen stimulation may have a protective effect on cells harboring variant WRN, allowing them to survive and proliferate for the prolonged period needed for tumor formation. Support for this hypothesis came from the following observations: (a) one SNP in WRN was significantly associated with breast cancer risk (P = 0.002); (b) haplotype and diplotype analyses, based on different combinations of multiple SNPs in WRN, revealed a strong association with breast cancer risk; (c) this association between risk and putative high-risk genotypes was stronger and more significant in women with a longer interval between menarche and first full-term pregnancy; and (d) the protective effect conferred by having a higher number of full-term pregnancy was only significant in women with homozygous or heterozygous wild-type WRN genotypes. This study provides support for the tumorigenic role of WRN in breast cancer development, suggesting that breast cancer can be driven by the aging associated with variant WRN, the tumorigenic contribution of which might be enhanced as a result of increased cell growth due to estrogen exposure.
 ...
PMID:Genetic variation in the premature aging gene WRN: a case-control study on breast cancer susceptibility. 1730 Dec 58


1 2 3 4 Next >>