Effect of dietary fat on codon 12 and 13 Ha-ras gene mutations in 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine–induced rat mammary gland tumors

Roberts‐Thomson, Sarah J.; Snyderwine, Elizabeth G.

doi:10.1002/(sici)1098-2744(199712)20:4<348::aid-mc4>3.0.co;2-f

Cited by 29 publications

(16 citation statements)

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“…Rasgrf2, a widely expressed guanine nucleotide exchange factor, promotes the release of bound GDP facilitating GTP binding and Ras activation. PhIP-induced rat mammary gland carcinomas are known to harbor H-ras mutations indicating that activation of the H-Ras pathway plays a role in these carcinomas (RobertsThomson and Snyderwine, 1997;Hokaiwado et al, 2001;Yu and Snyderwine, 2002). However, the observed changes in the expression of Rasa and Rasgrf2 were contrary to the changes expected if the H-Ras pathway were activated.…”

Section: Discussionmentioning

confidence: 99%

Allelic imbalance and altered expression of genes in chromosome 2q11–2q16 from rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Qiu

Shan

et al. 2003

Oncogene

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2-Amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), a compound found in cooked meat, is a mammary gland carcinogen in rats. Comparative genomic hybridization of PhIP-induced rat mammary gland carcinomas revealed loss in the centromeric region of 2q, a region known to carry the mammary carcinoma susceptibility 1 (Mcs1) gene and several other genes relevant to carcinogenesis. Allelic imbalance, specifically microsatellite instability and loss of heterozygosity, was examined in mammary gland carcinomas induced by PhIP in Sprague-Dawley (SD) Â Wistar Furth F1 hybrid rats. In a polymerase chain reaction (PCR)-based assay with 34 microsatellite markers coinciding to 2q11-2q16, nine markers revealed allelic imbalance. The frequency of imbalance in the tumors varied from 10 to 100% depending on the specific marker. However, none of the markers coinciding with the Mcs1 gene locus showed allelic imbalance, suggesting that alterations at this locus were not associated with PhIPinduced rat mammary gland cancer. The expression of several genes physically mapped to 2q11-2q16 and potentially involved in carcinogenesis including Ccnb (cyclin B1), Ccnh (cyclin H), Rasa (Ras GAP), Rasgrf2, Pi3kr1 (p85a), and Il6st (gp130) was also examined by quantitative real-time PCR and immunohistochemistry (IHC) across a large bank of PhIP-induced SD rat mammary gland carcinomas. By quantitative real-time PCR, the mRNA expression of Rasa, Pi3kr1, Ccnh, and Il6st in carcinomas was, respectively, 22-, 20-, three-and threefold higher in carcinomas than in control mammary gland tissues (Po0.05, Student's t-test). A statistically sixfold lower expression of Rasgrf 2 was detected in carcinomas whereas no significant change in Ccnb1 expression was observed. The findings from quantitative real-time PCR were confirmed by IHC for each gene. In addition, the proliferation index in mammary gland carcinomas as assessed by PCNA was found to correlate with the overexpression of Cyclin H by IHC analysis (Po0.05, Spearman Rank Order Correlation). The findings from the current study implicate molecular alterations in the proximal region of 2q in PhIP-induced rat mammary gland carcinomas.

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Section: Discussionmentioning

confidence: 99%

Allelic imbalance and altered expression of genes in chromosome 2q11–2q16 from rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Qiu

Shan

et al. 2003

Oncogene

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“…22 Briefly, genomic DNA was extracted, and a partial sequence of the H-ras gene was amplified by polymerase chain reaction (PCR). Mutations in the MnlI restriction site, spanning 4 bases at the junction of codons 12 and 13, protected the amplified fragment from digestion by MnlI.…”

Section: H-ras Gene Mutationmentioning

confidence: 99%

Cooperative induction of rat mammary cancer by radiation and 1‐methyl‐1‐nitrosourea via the oncogenic pathways involving c‐Myc activation and H‐ras mutation

Imaoka

Nishimura

Teramoto

et al. 2005

Intl Journal of Cancer

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Humans are continually exposed to various environmental carcinogens. Cancers may arise as a result of exposure to carcinogenic chemicals, ionizing radiation or a combination thereof. However, the mechanism of combined carcinogenesis has been only deduced from oncogenic actions of individual agents. Here, we analyzed experimental mammary carcinogenesis caused by a combination of radiation and a chemical carcinogen, 1‐methyl‐1‐nitrosourea (MNU). Seven‐week‐old female Sprague‐Dawley rats were divided into 4 groups: control, gγ‐irradiated (2 Gy), MNU‐treated (40 mg/kg, i.p.) and combined treatment of radiation with subsequent MNU after 3 days. Rats with palpable tumors were sacrificed at 50 weeks of age to collect tumors for histologic typing and mutational analysis of the H‐ras gene codon 12. The combined treatment induced adenocarcinomas, but not fibroadenomas, more efficiently than radiation or MNU alone. The H‐ras mutation was not seen in radiation‐induced carcinomas and was specific to MNU‐induced carcinomas in individually treated groups. In the combined treatment group, H‐ras‐mutated, but not nonmutated, tumors were more frequent and developed significantly earlier than in the MNU‐treated group. Significantly higher numbers of cells were stained for activated c‐Myc protein in gγ‐ray‐ and combined treatment‐induced cancers than in MNU‐induced cancers. These results indicate that combined exposure to the 2 carcinogens elicits an unexpected cooperativity in which pre‐irradiation enhances mammary carcinogenesis predominantly through the oncogenic pathway involving H‐ras, possibly by synergism with c‐Myc activation. © 2005 Wiley‐Liss, Inc.

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“…We found a very low rate of H-ras mutations (18%) and p53 mutations (10%) in adenocarcinomas of F344 rats induced by chronic administration of PhIP in a diet [Ushijima et al, 1995]. On the other hand, Roberts-Thomson and Snyderwine [1997] reported a high rate of H-ras mutations in mammary tumors of SD rats induced by 10 doses of PhIP administered by gastric intubation. This difference may be attributable to differences in the rat strains used and/or to differences in the PhIP administration protocols.…”

Section: Introductionmentioning

confidence: 92%

Studies on mammary carcinogenesis induced by a heterocyclic amine, 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine, in mice and rats

Nagao¹,

Ushijima

Watanabe

et al. 2002

Environ and Mol Mutagen

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Ten heterocyclic amines (HCAs) that are produced by heating amino acids, proteins, or proteinaceous food such as fish and meat were examined for carcinogenicity in rats and mice. Three of them, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f ]quinoline (MeIQ), and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), have been shown to induce mammary cancer in female F344 and/or SD rats, but none of the HCAs induced mammary cancer in CDF 1 mice. This report reviews our recent studies on mammary carcinogenesis of PhIP in various strains of mice and on the roles of genomic instability in the rat mammary carcinogenesis of PhIP. We demonstrated that the survival time from mammary adenocarcinomas was shorter in PhIP-treated BALB/c mice than that in the untreated control, and with a significantly higher incidence in the C.B-17 strain of mice compared with that of the control. To clarify mechanisms of mammary carcinogenesis, we examined genomic instability in rat mammary cancer induced by PhIP. Mammary cancers were induced in F344 ϫ SD F 1 rats harboring the lacI transgene, and two cell lines were established from two adenocarcinomas. They showed a greater than 10-fold higher frequency of spontaneous mutations than that of the primary culture of normal mammary epithelial cells, in the lacI transgene and the hprt endogenous gene during cell replication. Nucleotide sequencing revealed that almost all types of mutations were increased, with a remarkable increase of A:T 3 C:G mutation. This genomic instability was not attributed either to alterations of mismatch-repair enzymes or to p53. These mutational characteristics were also observed in the original tumors. Single-nucleotide instability (SNI) might be implicated in the mammary cancer induced by PhIP. Environ. Mol. Mutagen. 39:158 -164, 2002.

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Effect of dietary fat on codon 12 and 13 Ha-ras gene mutations in 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine–induced rat mammary gland tumors

Cited by 29 publications

References 29 publications

Allelic imbalance and altered expression of genes in chromosome 2q11–2q16 from rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Allelic imbalance and altered expression of genes in chromosome 2q11–2q16 from rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Cooperative induction of rat mammary cancer by radiation and 1‐methyl‐1‐nitrosourea via the oncogenic pathways involving c‐Myc activation and H‐ras mutation

Studies on mammary carcinogenesis induced by a heterocyclic amine, 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine, in mice and rats

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