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

Serum-free cultures of normal human buccal epithelial cells were transfected with a plasmid containing the SV40 T-antigen (SV40T) gene. Two major lines developed that showed extended lifespans (between 30 and 40 weeks) as compared with the controls (approximately 6 weeks). Continued growth through one or two crises generated several sublines. They expressed the epithelial marker keratin and also exhibited nuclear expression of SV40T. The lines showed abnormal karyotypes with both numerical and structural aberrations and variably responded to agents that normally inhibit growth and/or induce terminal differentiation, i.e. transforming growth factor-beta 1 and fetal bovine serum. One of the lines, termed SVpgC2a, developed into an apparently immortal line, since it had undergone more than 700 population doublings from over 2 years in culture. Further characterization of this line demonstrated its clonal origin, with integration of two copies of SV40T at the same site and the presence of both normal retinoblastoma and wild-type p53 proteins. This line showed high resistance to growth inhibition by transforming growth factor-beta 1 and serum similar to that shown by buccal carcinoma cell line SqCC/Y1. Neither SVpgC2a nor its parental lines were tumorigenic when injected into athymic nude mice, whereas the SqCC/Y1 cells induced tumors. The various lines with extended but finite lifespans, complemented by one immortalized line, which retained non-malignant properties upon extended culture, provide a battery of model systems that will be useful for studying mechanisms of human oral carcinogenesis.
Carcinogenesis 1995 Oct
PMID:Characterization of human buccal epithelial cells transfected with the simian virus 40 T-antigen gene. 758 60

Studies have shown an increased risk for breast cancer in the mothers of children suffering from retinoblastoma and osteosarcoma, suggesting a role for the retinoblastoma susceptibility (Rb) gene product in breast cancer. We now show that estradiol decreases the expression of Rb at the level of protein and messenger RNA (mRNA) in estrogen-dependent breast cancer cell lines. Treatment of MCF-7 cells with 10(-9) M estradiol for 48 h resulted in a 70% decrease in the level of Rb protein. Ribonuclease protection assays showed a 50% decrease in the steady state levels of Rb mRNA by 12 h and a 70% decrease in Rb mRNA by 24 h. Treatment with estradiol had no effect on the rate of Rb gene transcription or on Rb mRNA stability, but resulted in an increase in the steady state level of Rb mRNA in the nucleus. The effect of estradiol was inhibited by 10(-7) M 4-hydroxytamoxifen. In the absence of estradiol, the antiestrogens 4-hydroxytamoxifen and ICI 164,384 increased Rb mRNA by 50% over that in estrogen-depleted conditions. Estradiol regulation of Rb mRNA also occurred in other estrogen-dependent breast cancer cell lines. Insulin-like growth factor I, insulin, progestins, and epidermal growth factor had no effect on Rb expression. In summary, these results show that estradiol specifically regulates the expression of the Rb susceptibility gene product in hormone-dependent breast cancer by a posttranscriptional mechanism that occurs in the nucleus. The results from this study suggest that the negative regulation of Rb expression by estradiol, rather than Rb loss or mutation, may play an important role in breast carcinogenesis.
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PMID:Regulation of retinoblastoma gene expression in hormone-dependent breast cancer. 758 21

A cDNA of the rat retinoblastoma gene (RB) was prepared from total RNA of rat liver using reverse transcription-polymerase chain reaction (RT-PCR). The 4432-nt sequence isolated contained 2700-nt translated and 1732-nt 3'-untranslated regions (UTR). The isolated cDNA detected poly(A)+RNAs of 5.4 and 3.4 kb in rat liver and kidney by Northern blot hybridization. The nt sequence of the isolated cDNA had 85% homology with that of mouse and 73% with human. The 899-amino-acid (aa) sequence was 95% homologous to that of mouse and 90% to human. The aa sequences of two functional domains of oncoprotein-binding and ten putative phosphorylation sites regulating RB function were conserved in the three species. However, the 3'-UTR were less homologous among the three, and had polymorphism in three portions, even in rats. These polymorphisms were strain-specific and genetically segregated. Thus, the rat RB cDNA and its sequence information may be useful for clarifying the role of the RB protein and genetic linkage analysis in basic biomedical research using rats, especially in experimental carcinogenesis.
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PMID:Isolation and sequence polymorphism of a rat retinoblastoma (RB) cDNA. 766 85

Tumor suppressor genes have been found to have loss of function in a number of malignancies. This loss of function is believed to contribute to malignant transformation or metastatic spread. In the present study, expression of the retinoblastoma (RB) tumor suppressor gene was examined in cell lines and tumor tissue obtained from primary renal and metastatic sites in patients with metastatic renal cell carcinoma. Three of fifteen (20%) of informative renal carcinoma cell lines had loss of heterozygosity (LOH) in the RB gene (intron 20) detected by polymerase chain reaction analysis. Using restriction fragment length polymorphism (RFLP) analysis, 7 of 22 (32%) informative cell lines had LOH centromeric to the RB gene at the D13S1 locus. No LOH (0 of 7) was seen telomeric to the RB gene at the D13S2 locus. None of the 28 cell lines examined had decreased RB mRNA expression compared with short-term cultures of proximal renal tubular cells. Western blotting demonstrated phosphorylated and unphosphorylated forms of RB protein of expected molecular weight in all 41 cell lines (33 primary and 8 metastatic) examined. Twenty-nine primary cell lines and 6 metastatic cell lines all demonstrated normal immunohistochemical staining. Loss of RB immunohistochemical staining in paraffin-embedded tissue was detected in none of the primary tumors (0 of 30) or metastatic tumors (0 of 12). The absence of abnormalities of RB expression detected in these renal cell carcinomas suggests that abnormalities of the RB gene are not central to malignant transformation or progression in this tumor type; however, another tumor suppressor gene centromeric to the RB locus may be important in renal cell carcinogenesis.
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PMID:Loss of heterozygosity occurs centromeric to RB without associated abnormalities in the retinoblastoma gene in tumors from patients with metastatic renal cell carcinoma. 775 92

The oncogenic properties of the high risk human papillomaviruses (HPV) E7 protein are attributed to its interaction with the retinoblastoma susceptibility gene product RB1 and other related proteins. We report here the generation of a transgenic model expressing the E7 oncogene of HPV16 in thyroid follicular cells, under control of the bovine thyroglobulin gene promoter. Transgenics develop differentiated and functionally regulated thyroid goitres, due to thyroid cell proliferation and accumulation of colloid. On the background of this colloid goitre, the mice develop foci of more actively proliferating cells that become invasive and ultimately tend to loose their differentiation. Old mice display secondary tumour nodules that mimic the various histological aspects of the human differentiated thyroid cancers: the follicular and papillary carcinomas. The development of totally undifferentiated carcinoma is in contrast exceptional. We conclude that RB1, and/or related proteins, are responsible for the strict negative control of proliferation that characterizes the thyroid cell of the adult. Inactivation of these proteins results in a continuous growth of the thyroid, without affecting its differentiation, function and regulation. Given the high frequency of progression to highly malignant phenotypes, the retinoblastoma susceptibility and related genes are good candidates as targets for mutations or deletions in early steps of human thyroid carcinogenesis. The search for such mutations in human thyroid cancers will test if this hypothesis holds true.
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PMID:Differentiated carcinomas develop as a consequence of the thyroid specific expression of a thyroglobulin-human papillomavirus type 16 E7 transgene. 775 55

Inactivation of the retinoblastoma (Rb) gene has been implicated in the genesis and progression of a number of tumor types, including prostatic adenocarcinomas. We have analyzed a series of 46 surgically-resected human prostatic adenocarcinomas for allelic loss of the Rb gene with PCR amplification of a highly polymorphic region of the gene. 41 of 46 tumors (89%) were informative and 11 of these (27%) had lost one Rb allele. The relative frequency of this occurrence suggests that inactivation of the retinoblastoma gene may be an important event in prostate carcinogenesis.
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PMID:Allelic loss of the retinoblastoma gene in primary human prostatic adenocarcinomas. 784 65

Pancreatic islet tumors are relatively rare in the general population but occur frequently in patients with MEN 1. Delineation of the genetic events leading to neoplastic transformation of islet cells is at an early stage; but based on tumor deletion studies, it appears that inactivation of the MEN 1 gene is an early step in carcinogenesis for both sporadic and MEN 1-related tumors. Limited data also suggested a role for other tumor suppressors including the retinoblastoma, adenomatous polyposis coli, and Gorlin syndrome genes. Activation of oncogenes has not been identified in pancreatic islet tumors.
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PMID:Molecular mechanisms of neoplasia in multiple endocrine neoplasia type 1-related and sporadic tumors of the pancreatic islet cells. 791 19

Thirty-four of 51 (67%) primary retinoblastomas were analyzed cytogenetically to characterize the type of events that result in additional copies of the short arm of chromosome 6 and their implications in this malignancy. Of the 34 tumors studied, additional copies of 6p were found in 14 (41%). The most frequent mechanism involved to produce additional 6p chromosomes was the isochromosome i(6p) (65%). Other mechanisms were translocations of 6p to other chromosomes (14%), tetrasomy 6 (14%), and additional derived 6q- (7%). Although i(6p) is considered a chromosome rearrangement almost exclusive to retinoblastoma, its significance remains unknown in the carcinogenesis or the progression of retinoblastoma. Our work suggests strongly that the presence or absence of additional copies of 6p defines two categories of retinoblastoma; additional 6p is associated with an undifferentiated histologic degree and invasion of the optic nerve.
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PMID:Phenotype variants, malignancy, and additional copies of 6p in retinoblastoma. 792 58

The role of the retinoblastoma gene (RB1) in human gastric carcinogenesis is yet to be clarified. We report on the analysis of RB1 structure and protein (pRB) expression in gastric carcinomas using Southern blotting, Western blotting and immunohistochemistry. The relationship between pRB expression and cell proliferation was assessed by a proliferation marker (PCNA) in a subset of cases. Non-neoplastic mucosas were studied, as controls, by the same methodology. We found a close relationship between pRB expression and PCNA in non-neoplastic mucosas as well as in gastric carcinomas. All tumours were immunohistochemically positive for pRB, although with a variable proportion of non-immunoreactive cells. Carcinomas of the diffuse type showed absence of pRB expression in a larger proportion of neoplastic cells than carcinomas of the intestinal type (P < 0.05). Analysis of the RB1 structure using probe p68RS2.0 revealed allelic imbalance in 29% of informative cases. No homozygous deletions and/or rearrangements were detected with p68RS2.0 and cDNA probes. Western analysis revealed no abnormal patterns of pRB. Our data therefore suggest that major alterations affecting the RB1 gene are rather infrequent in human gastric carcinomas.
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PMID:Retinoblastoma gene structure and product expression in human gastric carcinomas. 794 78

The B6C3F1 mouse is used worldwide to gauge the carcinogenic hazard posed by chemicals to humans. An assessment of the ability of this rodent model to predict human neoplasia requires an evaluation of similarities and differences in the genetics of tumor formation between these two species. We examined 142 spontaneous and chemically-induced liver tumors isolated from the B6C3F1 mouse for losses of heterozygosity (LOH) at 78 polymorphic loci and compared these results to genetic changes known to occur in human hepatocellular carcinoma. Approximately a third of the 142 mouse tumors exhibited LOH, suggesting that tumor suppressor gene inactivation may be involved in the formation of mouse liver tumors. Most of the LOH observed was restricted to seven chromosome sites and most of the tumors that underwent LOH lost alleles from only one of those seven sites. The relatively few losses seen in these mouse tumors distinguished them from clinical stage human tumors in that, in the mouse tumors, interstitial deletions appeared more frequently than losses of whole chromosomes. Only four mouse tumors lost a whole chromosome. LOH occurred at loci of the mouse genome syntenic to areas of the human genome known to harbor the Wilms', retinoblastoma, APC, MCC and DCC tumor suppressor genes; these genes have never been associated with hepatocellular carcinomas. Losses observed on chromosomes 5 and 8 (syntenic to human chromosomes 4 and 16) suggest tumor suppressor genes that are common to hepatocellular carcinomas from both species, while losses on chromosome 9 suggest involvement of a previously unidentified tumor suppressor gene.
Carcinogenesis 1994 Aug
PMID:Loss of heterozygosity in spontaneous and chemically induced tumors of the B6C3F1 mouse. 805 44


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