Pathogenic characterization of 1-methyl-1-nitrosourea-induced mammary carcinomas in the rat

Lü, Junxuan; Jiang, Cheng; Mitrenga, Terry; Cutter, Gary; Thompson, Henry J.

doi:10.1093/carcin/19.1.223

Cited by 25 publications

(15 citation statements)

References 13 publications

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“…In our study, most of the palpable tumors were from the abdominal-inguinal glands. In other studies in which tumors were initiated with DMBA (68) or MNU (86,104) at day 50 of age, tumors were located mostly in the thoracic region. Asynchronous postnatal development of the cervical-thoracic versus abdominal-inguinal glands was suggested to explain the predominance of thoracic tumors (88).…”

Section: Discussionmentioning

confidence: 90%

Modulatory effects of neonatal exposure to TCDD, or a mixture of PCBs, p,p'-DDT, and p-p'-DDE, on methylnitrosourea-induced mammary tumor development in the rat.

Desaulniers

Leingartner

Russo

et al. 2001

Environ Health Perspect

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The role of organochlorine (OC) exposure in the etiology of breast cancer remains controversial. Thus, our objective was to determine whether the most abundant and toxic OCs found in human milk could, when ingested during the neonatal period, modulate the development of mammary tumors in the rat. We prepared a mixture composed of p,p'-dichlorodiphenyltrichloroethane (DDT), its major metabolite, p,p'-dichlorodiphenyldichloroethene (DDE), and 19 polychlorinated biphenyls (PCB) based on their concentrations found in the milk of Canadian women. Neonate rats at 1, 5, 10, 15, and 20 days of age were gavaged with this mixture, at 10, 100, and 1,000 times the amount that a human baby would consume. An additional group received 2.5 microg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg body weight (bw) by gavage at 18 days of age, instead of the mixture. On day 21, all treatment groups, except for a control group and a 1,000-mix group, received a single intraperitoneal injection of methylnitrosourea (MNU, 30 mg/kg bw), the initiator of the carcinogenic process. The average number of rats per treatment group was 33. Rats were sacrificed when their tumors reached 1 cm in size, or at 308 days of age. We prepared mammary tumors and mammary gland whole mounts for histologic analysis. There were no significant effects when only the malignant or only the benign tumors were considered. After all benign and malignant lesions were pooled, the number of mammary tumors differed among all MNU-treated groups (p = 0.02) with more lesions developing in the MNU-1,000[times] (median = 4.5; p = 0.05) and MNU-TCDD (median = 5.5; p = 0.07) compared to the MNU-0 rats (median = 2). Compared to the MNU-0 group, the percentage of rats that developed palpable tumors (benign plus malignant) was slightly higher (p = 0.06) in the MNU-TCDD group, but not in the MNU-1,000[times] group. The percentage of palpable tumors that were malignant was higher (p = 0.02) in the MNU-100[times] group (15/16, 94%) than in the MNU-0 group (10/18, 56%). The highest dose of the mixture delayed (p = 0.03) the development of tumors, but this was not observed with the MNU-TCDD treatment. These results suggest that neonatal exposure to high doses of organochlorines could favor the development of MNU-induced mammary lesions, but also delays the development of palpable tumors in the rat.

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Section: Discussionmentioning

confidence: 90%

Modulatory effects of neonatal exposure to TCDD, or a mixture of PCBs, p,p'-DDT, and p-p'-DDE, on methylnitrosourea-induced mammary tumor development in the rat.

Desaulniers

Leingartner

Russo

et al. 2001

Environ Health Perspect

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“…The literature generally reports tumor mutations as the percentage of tumors positive for the mutation, usually as determined by DNA sequencing. When methods more sensitive than DNA sequencing are used, larger percentages of positives are reported [Keohavong et al, 1997;Fox et al, 1998;Lu et al, 1998;Sieben et al, 2006]. It was expected that the ACB-PCR assay would detect a percentage of tumors with MFs approaching 0.5 (the MF of a pure population of heterozygous mutant cells), along with a portion of the tumors without mutation.…”

Section: Lessons Learned During Initial Validation Of Oncomutation Asmentioning

confidence: 99%

Oncomutations as biomarkers of cancer risk

Parsons

Myers

Meng

et al. 2010

Environ and Mol Mutagen

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Cancer risk assessment impacts a range of societal needs, from the regulation of chemicals to achieving the best possible human health outcomes. Because oncogene and tumor suppressor gene mutations are necessary for the development of cancer, such mutations are ideal biomarkers to use in cancer risk assessment. Consequently, DNA-based methods to quantify particular tumor-associated hotspot point mutations (i.e., oncomutations) have been developed, including allele-specific competitive blocker-PCR (ACB-PCR). Several studies using ACB-PCR and model mutagens have demonstrated that significant induction of tumor-associated oncomutations are measureable at earlier time points than are used to score tumors in a bioassay. In the particular case of benzo[a]pyrene induction of K-Ras codon 12 TGT mutation in the A/J mouse lung, measurement of tumor-associated oncomutation was shown to be an earlier and more sensitive endpoint than tumor response. The measurement of oncomutation by ACB-PCR led to two unexpected findings. First, oncomutations are present in various tissues of control rodents and "normal" human colonic mucosa samples at relatively high frequencies. Approximately 60% of such samples (88/146) have mutant fractions (MFs) >10(-5), and some have MFs as high as 10(-3) or 10(-4). Second, preliminary data indicate that oncomutations are present frequently as subpopulations in tumors. These findings are integrated into a hypothesis that the predominant preexisting mutations in particular tissues may be useful as generic reporters of carcinogenesis. Future research opportunities using oncomutation as an endpoint are described, including rodent to human extrapolation, dose-response assessment, and personalized medicine.

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“…The MNU induction model is a standard paradigm for studying breast tumors in rats. (9)(10)(11)(12) Tumors are induced at rates exceeding 50%…”

Section: Experimental Modelmentioning

confidence: 99%

Breast tumors induced by N-methyl-N-nitrosourea are damaging to bone strength, structure, and mineralization in the absence of metastasis in rats

Thorpe

Valentine

Moulton

et al. 2010

Journal of Bone and Mineral Research

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Current theory on the influence of breast cancer on bone describes metastasis of tumor cells to bone tissue, followed by induction of osteoclasts and bone degradation. Tumor influences on bone health in pre-or nonmetastatic models are unknown. Female rats (n ¼ 48, 52 days old) were injected with N-methyl-N-nitrosourea (MNU) to induce breast cancer. Animals were euthanized 10 weeks later, and tumors were weighed and classified histologically. Right femurs were extracted for testing of bone mineral density (BMD) by dual X-ray absorptiometry (DXA), bone mechanical strength by three-point bending and femoral neck bending tests, and structure by microcomputed tomography (mCT). Of 48 rats, 22 developed one or more tumors in response to MNU injection by 10 weeks. Presence of any tumor predicted significantly poorer bone health in 17 of 28 measures. In tumored versus nontumored animals, BMD was adversely affected by 3%, force at failure of the femoral midshaft by 4%, force at failure of the femoral neck by 12%, and various trabecular structural parameters by 6% to 27% (all p < .05). Similarly, greater tumor burden, represented by total tumor weight, adversely correlated with bone outcomes: r ¼ À0.51 for BMD, À0.42 and À0.35 for femur midshaft force and work at failure, and between 0.36 and 0.59 (absolute values) for trabecular architecture (all p < .05). Presence of MNU-induced tumors and total tumor burden showed a negative association with bone health of the femur in rats in the absence of metastasis. Further study is required to elucidate mechanisms for this association. ß

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Pathogenic characterization of 1-methyl-1-nitrosourea-induced mammary carcinomas in the rat

Cited by 25 publications

References 13 publications

Modulatory effects of neonatal exposure to TCDD, or a mixture of PCBs, p,p'-DDT, and p-p'-DDE, on methylnitrosourea-induced mammary tumor development in the rat.

Modulatory effects of neonatal exposure to TCDD, or a mixture of PCBs, p,p'-DDT, and p-p'-DDE, on methylnitrosourea-induced mammary tumor development in the rat.

Oncomutations as biomarkers of cancer risk

Breast tumors induced by N-methyl-N-nitrosourea are damaging to bone strength, structure, and mineralization in the absence of metastasis in rats

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