RESUMO
Inherited mutant alleles of familial tumour suppressor genes predispose individuals to particular types of cancer. In addition to an involvement in inherited susceptibility to cancer, these tumour suppressor genes are targets for somatic mutations in sporadic cancers of the same type found in the familial forms. An exception is BRCA1, which contributes to a significant fraction of familial breast and ovarian cancer, but undergoes mutation at very low rates in sporadic breast and ovarian cancers. This finding suggests that other genes may be the principal targets for somatic mutation in breast carcinoma. A second, recently identified familial breast cancer gene, BRCA2 (refs 5-8), accounts for a proportion of breast cancer roughly equal to BRCA1. Like BRCA1, BRCA2 behaves as a dominantly inherited tumour suppressor gene. Individuals who inherit one mutant allele are at increased risk for breast cancer, and the tumours they develop lose the wild-type allele by heterozygous deletion. The BRCA2 coding sequence is huge, composed of 26 exons that span 10,443 bp. Here we investigate the rate of BRCA2 mutation in sporadic breast cancers and in a set of cell lines that represent twelve other tumour types. Surprisingly, mutations in BRCA2 are infrequent in cancers including breast carcinoma. However, a probable germline mutation in a pancreatic tumour cell line suggests a role for BRCA2 in susceptibility to pancreatic cancer.
Assuntos
Carcinoma/genética , Mutação , Proteínas de Neoplasias/genética , Neoplasias/genética , Fatores de Transcrição/genética , Proteína BRCA2 , Sequência de Bases , Neoplasias da Mama/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Heterozigoto , Humanos , Incidência , Dados de Sequência Molecular , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Reação em Cadeia da Polimerase/métodos , Análise de Sequência de DNA , Células Tumorais CultivadasRESUMO
The distribution of selenium between the plasma fractions was investigated in guinea pigs fed various levels (basal, 0.5, 1.0, 2.0, 4.0, 6.0 and 8.0 mg Se/kg) of dietary selenomethionine (Semet) and in humans living in different areas of China with different selenium status. There was a corresponding increase of selenium concentration in liver, kidney, brain, testis, spleen, heart and muscle with each increase of dietary selenium, but there were no increases of glutathione peroxidase (GPX) activity in liver, brain, testis, heart or muscle in pigs fed any of the selenium levels as compared to controls fed a basal commercial diet. On a percentage distribution basis, the selenium in selenoprotein P decreased and that in the albumin fraction increased with increased dietary intakes of selenium as Semet. The ratios of selenium to albumin in either the plasma or the albumin fractions increased with each increase in dietary selenium. The greatest percentage of selenium was in the albumin fraction of Chinese living in the high selenium areas whereas the greatest amount was in the selenoprotein P fraction in subjects living in deficient and adequate areas of China. Increases in the ratios of selenium to albumin in either the plasma or the albumin fraction also occurred with increases of selenium intake of these subjects. The results indicate that the distribution of selenium in plasma fractions reflect the levels of dietary intakes of Semet.
Assuntos
Selênio/administração & dosagem , Selênio/sangue , Adulto , Animais , Biomarcadores , Dieta , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Feminino , Glutationa Peroxidase/sangue , Cobaias , Humanos , Masculino , Selênio/toxicidade , Albumina Sérica/metabolismo , Distribuição TecidualRESUMO
BACKGROUND/OBJECTIVES: Risk for developing osteoporosis increases in Asia. The purpose of the study was to evaluate the impact of a high-calcium vitamin D fortified milk (HCM) intervention on parathyroid hormone (PTH) levels, vitamin D status and markers of bone turnover in postmenopausal Chinese women. SUBJECTS/METHODS: Sixty three women (>55 years) were assigned to receive two servings of either a calcium/vitamin D fortified milk or a control drink for 12 weeks. PTH, serum 25 (OH)D levels, C-telopeptide of type I collagen (CTX) levels and procollagen type I N-terminal propeptide (PINP) were measured at baseline, 2, 8 and 12 weeks of supplementation. RESULTS: Daily calcium intake at baseline ranged between 260 and 482 mg for the HCM, and 252 and 692 mg for the control group. HCM improved serum 25 (OH)D levels significantly (33.13-39.49 nmol/l), while remaining similar in the control group (29.27-28.21 nmol/l). The difference between the groups were significant at week 2, 8 and 12. The percentage change in PTH levels in the HCM group was significant from week 2 onwards compared to the control drink (P<0.017, P<0.05 and P<0.001 at weeks 2, 8 and 12, respectively). Plasma CTX of the HCM group reduced by 25% between weeks 0 and 2, remaining significantly lower and at similar levels up to week 12. The difference between the HCM and control group for PINP reached significance at weeks 8 (P=0.011) and 12 (P=0.003). CONCLUSIONS: The HCM intervention significantly improved vitamin D status and reduced bone turnover over 12 weeks in postmenopausal Chinese women.
Assuntos
Reabsorção Óssea/prevenção & controle , Cálcio da Dieta/uso terapêutico , Alimentos Fortificados , Micronutrientes/uso terapêutico , Leite , Osteoporose Pós-Menopausa/prevenção & controle , Vitamina D/uso terapêutico , Idoso , Animais , Biomarcadores/sangue , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/sangue , Cálcio da Dieta/administração & dosagem , Cálcio da Dieta/farmacologia , China , Colágeno Tipo I/sangue , Feminino , Humanos , Micronutrientes/sangue , Micronutrientes/farmacologia , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/sangue , Hormônio Paratireóideo/sangue , Fragmentos de Peptídeos/sangue , Peptídeos/sangue , Pró-Colágeno/sangue , Vitamina D/análogos & derivados , Vitamina D/sangue , Vitamina D/farmacologiaRESUMO
Weanling Wistar rats were fed on diets prepared from grain from areas deficient in I and Se where Keshan disease in endemic. Rats were divided into four groups, each of twelve rats, and received a diet supplemented with: I, Se, I + Se or nothing. At 8 weeks after weaning, myocardial alpha-glycerophosphate dehydrogenase (EC 1.1.1.8; alpha-GPD) activity and indices of Se and thyroid hormone status were determined. The group supplemented with iodine had increased plasma thyroxine levels. There was no difference in plasma triiodothyronine concentration between the groups but triiodothyronine levels in heart were reduced in the Se-supplemented group. Se supplementation increased myocardial glutathione peroxidase activity (EC 1.11.1.9) and the type I 5'-deiodinase (EC 3.8.1.4) activity in rat liver, but no type I 5'-deiodinase activity was detected in heart. alpha-GDP activity in heart was increased in group supplemented with Se, I or both. There was a significant relationship (P < 0.05) between myocardial alpha-GDP activity and plasma thyroxine levels but not between alpha-GDP and myocardial glutathione peroxidase activity. The results indicate that iodine may be more important than Se in energy metabolism in the myocardium, which may give a new insight for the study of the aetiology of Keshan disease in areas where foodstuffs are deficient in both Se and I.
Assuntos
Cardiomiopatias/etiologia , Glicerolfosfato Desidrogenase/metabolismo , Iodo/deficiência , Miocárdio/metabolismo , Selênio/deficiência , Hormônios Tireóideos/metabolismo , Análise de Variância , Animais , Cardiomiopatias/enzimologia , Cardiomiopatias/metabolismo , Metabolismo Energético , Iodo/administração & dosagem , Fígado/enzimologia , Fígado/metabolismo , Masculino , Modelos Biológicos , Miocárdio/enzimologia , Ratos , Ratos Wistar , Selênio/administração & dosagem , Hormônios Tireóideos/sangue , Tiroxina/sangue , Tiroxina/metabolismo , Tri-Iodotironina/sangue , Tri-Iodotironina/metabolismo , DesmameRESUMO
We have performed a homozygous deletion screen on 268 candidate genes in 90 human tumor cell lines derived from multiple types of cancers. Most of the candidate genes investigated have been proposed to be involved in cellular processes that are germane to cancer progression, such as cell cycle control, genome maintenance, chromatin remodeling, cell adhesion, and apoptosis. We have detected novel homozygous deletions affecting four independent loci: Brahma-related gene (SMARCA4) on chromosome 19p in the TSU-Pr1 prostate and A427 lung carcinoma lines, Map Kinase Kinase 3 (MAP2K3) on 17q in the NCI-H774 lung tumor cell line, TMPRSS2 on 21q in the Bx PC-3 pancreatic carcinoma line, and Cadherin 6 (CDH6) on 5p in the SK-LU-1 lung carcinoma line. Subsequent analyses of the coding sequences of these four genes using cDNAs from a panel of tumor cell lines revealed multiple sequence variants. The results of this mutation study serve to demonstrate the feasibility of performing high-throughput screens of candidate genes in tumor cell lines to identify genes that may be targeted for mutation during the development of cancer.
Assuntos
Predisposição Genética para Doença/genética , Mutação , Neoplasias/genética , Caderinas/genética , Mapeamento Cromossômico , Análise Mutacional de DNA , DNA Complementar/química , DNA Complementar/genética , DNA de Neoplasias/química , DNA de Neoplasias/genética , Deleção de Genes , Homozigoto , Humanos , MAP Quinase Quinase 3 , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Proteínas Tirosina Quinases/genética , Serina Endopeptidases/genética , Células Tumorais CultivadasRESUMO
Human CDC14A is a dual-specificity phosphatase that shares sequence similarity with the recently identified tumor suppressor, MMAC1/PTEN/TEP1. By radiation hybrid mapping, we localized CDC14A to chromosome band 1p21, a region that has been shown to exhibit loss of heterozygosity in highly differentiated breast carcinoma and malignant mesothelioma. We have mapped the exon-intron structure of CDC14A gene and found an in-frame ATG at 14 codons upstream of the previously reported start site (GenBank Accession No. AF000367). In screening a panel of 136 cDNAs from tumor cell lines for coding mutations, we have identified a 48-bp in-frame deletion in the cDNA of the breast carcinoma cell line, MDA-MB-436. This deletion is the result of an acceptor splice site mutation (AG to AT) in intron 12 that causes the skipping of exon 13 in the gene. Loss of expression of the wildtype allele in the same breast cell line supports the possibility that CDC14A may be a tumor suppressor gene that is targeted for inactivation during tumorigenesis.