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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rat is an extremely valuable model for studies of inherited susceptibility to breast cancer because the characteristics of rat mammary cancer and human breast cancer are so similar. There are now several rat models for studying sensitivity versus resistance, or cell autonomy versus non-cell-autonomy, for spontaneous and induced mammary cancers. It is known that the tumor-resistant Cop [20, 21] and WKy [8] strains carry dominant resistance genes that inhibit both spontaneous and induced mammary tumors. The WF and SD strains are known to carry dominant sensitivity genes that appear to increase susceptibility to induced but not spontaneous mammary tumors. The presence of both resistance and sensitivity genes in the Cop strain is intriguing, and provides a unique model for studying the interactions of both types of genes. It appears that the resistance genes together are at least partially dominant over the sensitivity gene in this model since the F1 rats develop only a few tumors. Yet another strain, the F344, has an intermediate sensitivity and has been shown to carry neither sensitivity or resistance genes. Thus, all these models and data indicate that sensitivity genes are not necessary for the development of mammary tumors, and neither are they sufficient. However, loss of resistance gene function is necessary but is not sufficient for mammary tumor development. Studies have shown that the sensitivity and resistance genes act directly within the mammary epithelial cells rather than globally in the rat. The products of these genes also do not appear to act at early steps in the carcinogenic process because there have been no observed effects of these genes on carcinogen metabolism or DNA adduct formation. It would appear that these genes act at later stages of mammary carcinogenesis. Identification and isolation of these genes should aid our understanding of the inherited components of human breast cancer. With the increasing availability of genetic markers and large-insert libraries for the rat genome, genetic and physical mapping studies are now a reality for the genes involved in mammary carcinogenesis of the rat. Such studies have already revealed the multigenic nature of this cancer, supporting the idea that the limited penetrance of BRCA1 and BRCA2 in human breast cancer is due to loci that modify the effects of the sensitivity genes. Assuming that human homologues of the Mcs genes exist, cloning the genes and defining the human homologues may provide a way to identify the risk for breast cancer development in women. Analysis of the function of such genes may also lead to the development of new drugs for chemoprevention and/or therapy of this lethal disease.
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PMID:The genetic components of susceptibility to breast cancer in the rat. 1037 59

Somatic changes in the genome of breast cancer cells include amplifications, deletions and gene mutations. Several chromosome regions harboring known oncogenes are found amplified in breast tumors. Despite the high number of chromosome regions deleted in breast tumors the functional relationship to known genes at these locations and cancer growth is mainly undiscovered. Mutations in two tumor suppressor genes (TSG) have been described in a subset of breast carcinomas. These TSG are the TP53, encoding the p53 transcription factor, and the CDH1, encoding the cadherin cell adhesion molecule. Breast tumors of patients with a germ-line mutation in the BRCA1 or BRCA2 gene have an increase of additional genetic defects compared with sporadic breast tumors. This higher frequency of genetic aberrations could pinpoint genes that selectively promote tumor progression in individuals predisposed to breast cancer due to BRCA1 or BRCA2 germ-line mutations. Accumulation of somatic genetic changes during tumor progression may follow a specific and more aggressive pathway of chromosome damage in these individuals. Although the sequence of molecular events in the progression of breast tumor is poorly understood the detected genetic alterations fit the model of multistep carcinogenesis in both sporadic and hereditary breast cancer. This review will focus on the genetic lesions within the breast cancer cell.
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PMID:Molecular genetics of breast cancer progression. 1044 15

Inherited mutations in the BRCA1 gene confer increased susceptibility to breast and ovarian cancer. Its role in sporadic carcinogenesis is not well defined. Somatic mutations in breast cancers have not been reported and to date there are only three reports of somatic mutations in sporadic ovarian cancers. To investigate the contribution of BRCA1 mutations to sporadic breast and ovarian cancer in the Chinese population, we analysed 62 samples from Chinese women using the protein truncation test. There were 40 cases of breast cancer under age 50 and 22 cases of ovarian cancer, all unselected for family history. There was no age selection for the ovarian cancers. We found two somatic BRCA1 mutations in exon 11, one in a breast cancer and the other in an ovarian cancer, both of which result in truncated proteins. Our results indicate that somatic BRCA1 mutations, like somatic mutations in the BRCA2 gene, though very rare, can be found in both breast and ovarian cancers and support a tumor suppressor function for BRCA1 in sporadic tumors.
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PMID:Somatic mutations in the BRCA1 gene in Chinese sporadic breast and ovarian cancer. 1046 10

We have investigated frameshift mutations in exonic repeats in the ATR, BRCA1, BRCA2, PTCH, CTCF, Cx26, NuMa and TGFbetaRII genes, using human tumor samples from stomach, esophagus, breast and skin and melanoma, as well as colon cancer and endometrial cancer cell lines (125 samples in total). We developed a sensitive method to detect mutations in the repeats, using the introduction of an artificial restriction site into a repeat. The method detects a single mutant among 10(3) normal genes. Thus, an alteration in a repeated sequence can be detected unambiguously. The (A)(8) repeat of BRCA2 was found mutated in only two of five colon cell lines with microsatellite instability (MI(+)). The ATR gene has an (A)(10) repeat which was altered in two of three MI(+) stomach cancer samples and one of three MI(+) endometrial cell lines. The TGFbetaRII gene [with an (A)(10) repeat] had the maximal frequency of mutations: 10 out of 13 MI(+) samples. At least one sample from all types of cancers, except melanomas, was positive for TGFbetaRII gene mutations. No mutations were found in repeats in the BRCA1, PTCH, CTCF, NuMA and Cx26 genes in any types of tumors examined. In conclusion, our study indicates that repeats were altered only in MI(+) cells and that the mutation frequencies in the genes studied differ among tumor types. Based on these results, we discuss meaningful and meaningless alterations in exonic repeats.
Carcinogenesis 1999 Nov
PMID:A novel sensitive method to detect frameshift mutations in exonic repeat sequences of cancer-related genes. 1054 25

The identification of breast cancer susceptibility genes, such as BRCA1, BRCA2, ATM, and p53, has been accompanied by the examination of the effects of radiation in combination with genetic mutations at these loci. Women at high risk for developing breast cancer may respond differently than the general population to low- and high-dose radiation exposures associated with screening and treatment. Epidemiologic studies are being performed to investigate the effects of radiation on subsequent breast cancer development in genetically predisposed individuals. Mouse strains with specific genetic modifications are being created to study the consequence of both inherited mutations and radiation on mammary gland carcinogenesis. Finally, studies investigating DNA damage-response pathways after radiation exposure are being performed. Recent work on the effects of several known or suspected breast cancer susceptibility genes, alone or in combination with radiation, is presented here, and directions for future research are considered.
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PMID:Breast cancer: genetic predisposition and exposure to radiation. 1055 88

The identification of the breast/ovarian susceptibility genes, BRCA1 and BRCA2 was an important advancement in the field of breast and ovarian cancer research. About 40-50% of site specific hereditary breast cancers and up to 80% of hereditary breast-ovarian cancers result from mutations in the BRCA1 gene. Although BRCA1 mediates multiple functions in the cell, including a role in DNA damage repair and gene transcription, the role of BRCA1 has not completely been elucidated yet. It has been suggested that mutational inactivation of TP53 may be required for BRCA1-associated tumorigenesis. Several studies have shown that TP53 is more frequently inactivated in BRCA1-associated tumors than in sporadic breast or ovarian cancer. Up to 90% of BRCA1-associated tumors harbor either a TP53 mutation and/or TP53 protein accumulation. The remaining tumors may well have other alterations affecting the cell cycle checkpoint. Loss of this checkpoint may be obligatory for BRCA1-tumorigenesis. In this review, we discuss recent advances in BRCA1-research and stress the pivotal role TP53 may play in BRCA1-associated carcinogenesis.
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PMID:Is TP53 dysfunction required for BRCA1-associated carcinogenesis? 1058 Aug 47

Loss of heterozygosity (LOH) on chromosome 13q is one of the most common genetic alterations in hepatocellular carcinoma (HCC) and might be involved in liver cancer development through inactivation of tumour suppressor genes. In order to narrow down the region of 13q loss, we examined the pattern of loss of heterozygosity (LOH) in tumours from 88 HCC patients, using 18 microsatellite markers on 13q. Thirty-eight of the 88 tumours (43%) showed LOH for at least one marker. Of these, two tumours (5%) showed 13q whole arm allelic loss, while the remaining 36 tumours (95%) had partial allelic loss. The LOH pattern defined by the 36 tumours suggested the existence of at least three different smallest common deleted regions which might be involved in the carcinogenesis of HCC. The first, the most centromeric in the 13q12.3 is, close to the BRCA2 gene, defined by D13S171; the second, the most telomeric region in the 13q31-32 band, is defined by D13S154 and D13S157; the third, the intermediate region at 13q14.3, which is near the RB gene, is defined by loci D13S268. The rate of LOH at 13q31-32 was significantly higher in Hepatitis B-surface antigen (HBsAg)-positive patients than HBsAg-negative HCC patients, pointing to a candidate gene related to the development of HBsAg-positive HCCs.
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PMID:Loss of heterozygosity at chromosome 13q in hepatocellular carcinoma: identification of three independent regions. 1067 21

Ovarian cancer remains the leading cause of death from gynecologic malignancy in Western countries. This cancer results from a succession of genetic alterations involving oncogenes and tumor suppressor genes which have a critical role in normal cell growth regulation. Mutations and/or overexpression of three oncogenes, HER-2/neu, c-myc and K-ras, and of the tumor suppressor gene p53, have frequently been observed in sporadic ovarian cancer. In the context of high risk families, the most frequently involved genes are BRCA1 and BRCA2. We review the function of these different proteins, the incidence of mutations in their genes in carcinogenesis and as potential prognostic factors in sporadic and hereditary ovarian cancer.
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PMID:Major oncogenes and tumor suppressor genes involved in epithelial ovarian cancer (review). 1067 91

BRCA2 is a tumor suppressor gene whose germline mutations increase the lifetime risk of breast cancer. BRCA2 encodes a large nuclear protein involved in DNA repair, but the location of its functional domain has been unclear. Here, we report nuclear localization signals (NLSs) of the BRCA2 protein. By expressing various portions of the BRCA2 protein tagged with enhanced green fluorescent protein in HeLa cells, we show that the C-terminal domain is necessary for nuclear localization. Two regions in the C-terminal domain were identified with functional NLSs by site-directed mutagenesis analyses. The NLSs locate between the germline mutation found in the most downstream position and the polymorphic stop codon, suggesting that defects in the proper nuclear transport of the BRCA2 protein are causative of carcinogenesis. Our data thus provide a possible explanation for the high frequency of frame-shift and nonsense mutations in BRCA2 of hereditary breast cancer patients.
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PMID:Nuclear localization signals of the BRCA2 protein. 1073 23

It is well accepted that cancer arises in a multistep fashion in which exposure to environmental carcinogens is a major etiological factor. The aim of this work was to establish an experimental breast cancer model in order to understand the mechanism of neoplastic transformation induced by high LET radiation in the presence of 17beta-estradiol (E). Immortalized human breast cells (MCF-10F) were exposed to low doses of high LET alpha particles (150 keV/microm) and subsequently cultured in the presence or absence of E for periods of up to 10 months post-irradiation. MCF-10F cells irradiated with either a single 60 cGy dose or 60/60 cGy doses of alpha particles showed gradual phenotypic changes including altered morphology, increase in cell proliferation relative to the control, anchorage-independent growth and invasive capability before becoming tumorigenic in nude mice. In alpha particle-irradiated cells and in those cells subsequently cultured in the presence of E, increased BRCA1, BRCA2 and RAD51 expression were detected by immunofluorescence staining and quantified by confocal microscopy. These studies showed that high LET radiation such as that emitted by radon progeny, in the presence of estrogen, induced a cascade of events indicative of cell transformation and tumorigenicity in human breast epithelial cells.
Carcinogenesis 2000 Apr
PMID:Establishment of a radiation- and estrogen-induced breast cancer model. 1075 14


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