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Excess weight gain accelerates 1-methyl-1-nitrosourea-induced mammary carcinogenesis in a rat model of premenopausal breast cancer.

ABSTRACT: In contrast to the null effects generally reported, high-risk premenopausal women (Gail score ?1.66) enrolled in the Breast Cancer Prevention P-1 Trial were recently reported to be at increased risk for breast cancer when overweight (HR = 1.59) or obese (HR = 1.70). To investigate this clinical observation in a preclinical setting, ovary-intact female rats were intraperitoneally injected with 50 mg/kg 1-methyl-1-nitrosourea at 21 days of age to simulate premenopausal women with increased risk. Two commercially available strains of Sprague-Dawley rat (Taconic Farms) were used, which are dietary resistant (DR) or dietary susceptible (DS) to excess weight gain when fed a purified diet containing 32% kcal from fat, similar to levels consumed by the typical American woman. DS rats were approximately 15.5% heavier than DR rats at study termination and plasma leptin indicated a marked difference in adiposity. DS rats had higher incidence (26% increase), multiplicity (2.5-fold increase), and burden (5.4-fold increase) of mammary carcinomas with a concomitant reduction in cancer latency (16% earlier detection) compared with DR rats (P < 0.001 for all analyses), and displayed a higher proportion of hormone receptor negative tumors compared with DR rats [OR = 1.78; 95% confidence interval (CI), 0.83-3.81]. Circulating levels of several breast cancer-risk factors, including leptin, adiponectin:leptin ratio, insulin, insulin-like growth factor (IGF)-1, IGF-1:IGF-1 binding protein-3 ratio, and calculated insulin resistance (HOMA-IR) were negatively impacted in DS rats (P < 0.05 for all analyses). These findings support further investigation of the effects of excess weight in high-risk premenopausal women and demonstrate a useful preclinical model for rapid evaluation of mechanistic hypotheses.

SUBMITTER: Matthews SB

PROVIDER: S-EPMC3955111 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Excess weight gain accelerates 1-methyl-1-nitrosourea-induced mammary carcinogenesis in a rat model of premenopausal breast cancer.

Matthews Shawna B SB Zhu Zongjian Z Jiang Weiqin W McGinley John N JN Neil Elizabeth S ES Thompson Henry J HJ

Cancer prevention research (Philadelphia, Pa.) 20140117 3

In contrast to the null effects generally reported, high-risk premenopausal women (Gail score ≥1.66) enrolled in the Breast Cancer Prevention P-1 Trial were recently reported to be at increased risk for breast cancer when overweight (HR = 1.59) or obese (HR = 1.70). To investigate this clinical observation in a preclinical setting, ovary-intact female rats were intraperitoneally injected with 50 mg/kg 1-methyl-1-nitrosourea at 21 days of age to simulate premenopausal women with increased risk. T ...[more]

PMID: 24441676

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Project description:BackgroundChemically induced animal models of breast cancer (BC) using N-methyl-N-nitrosourea (MNU) have been widely used in preclinical research. The conventional approach entails intraperitoneal (i.p) or intravenous injection of a carcinogen, leading to tumor induction at unpredictable locations. This study aimed to establish a modified MNU-induced rat mammary tumor model using intraductal (i.duc) administration and to evaluate its biological behavior, morphology, and response to chemotherapy drugs.MethodsIn a pilot experiment, female Sprague-Dawley (SD) rats were injected with either i.duc MNU or vehicle to test the feasibility of this approach. We explored the appropriate dosage for stable tumor formation in pubescent female SD rats by testing a single i.duc dose of MNU (0.5, 1.0 and 2.0 mg) or vehicle.ResultsAn i.duc injection of 20 µL (1 mg/per duct) MNU in the fourth rat mammary gland induced stable carcinomas in situ. Immunohistochemical (IHC) analysis showed positive expression of estrogen receptor (ER), negative expression of human epidermal growth factor receptor 2 (Her-2), and low expression of Ki-67. Histopathology revealed atypical hyperplasia in the mammary gland 4 weeks after carcinogen injection, developing into carcinoma in situ 5-6 weeks after treatment, with loss of α-SMA and calponin expressions during tumor progression. Albumin-bound paclitaxel (nab-PTX) was injected i.duc and intravenously (i.v) 5 weeks after administration of MNU. The tumor growth rate of the nab-PTX i.duc-treated group was lower than in the i.v and control groups. The number of TUNEL-positive apoptotic cells was significantly higher in the nab-PTX i.duc-treated group.ConclusionsUsing i.duc MNU (20 µL, 1 mg) to establish a rat mammary tumor model resulted in a predictable location in the rat mammary gland and exhibited better consistency; i.duc administration of nab-PTX permitted a smaller drug dose, but produced a better drug response, than i.v injection.

Project description:1. N[(14)C]-Methyl-N-nitrosourea, [(14)C]dimethylnitrosamine, [(14)C]dimethyl sulphate and [(14)C]methyl methanesulphonate were injected into rats, and nucleic acids were isolated from several organs after various time-intervals. Radioactivity was detected in DNA and RNA, partly in major base components and partly as the methylated base, 7-methylguanine. 2. No 7-methylguanine was detected in liver DNA from normal untreated rats. 3. The specific radioactivity of 7-methylguanine isolated from DNA prepared from rats treated with [(14)C]dimethylnitrosamine was virtually the same as that of the dimethylnitrosamine injected. 4. The degree of methylation of RNA and DNA produced in various organs by each compound was determined, and expressed as a percentage of guanine residues converted into 7-methylguanine. With dimethylnitrosamine both nucleic acids were considerably more highly methylated in the liver (RNA, about 1% of guanine residues methylated; DNA, about 0.6% of guanine residues methylated) than in the other organs. Kidney nucleic acids were methylated to about one-tenth of the extent of those in the liver, lung showed slightly lower values and the other organs only very low values. N-Methyl-N-nitrosourea methylated nucleic acids to about the same extent in all the organs studied, the amount being about the same as that in the kidney after treatment with dimethylnitrosamine. In each case the RNA was more highly methylated than the DNA. Methyl methanesulphonate methylated the nucleic acids in several organs to about the same extent as N-methyl-N-nitrosourea, but the DNA was more highly methylated than the RNA. Dimethyl sulphate, even in toxic doses, gave considerably less methylation than N-methyl-N-nitrosourea in all the organs studied, the greatest methylation being in the brain. 5. The rate of removal of 7-methylguanine from DNA of kidneys from rats treated with dimethylnitrosamine was compared with the rate after treatment of rats with methyl methanesulphonate. No striking difference was found. 6. The results are discussed in connexion with the organ distribution of tumours induced by the compounds under study and in relation to the possible importance of alkylation of cellular components for the induction of cancer.

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Excess weight gain accelerates 1-methyl-1-nitrosourea-induced mammary carcinogenesis in a rat model of premenopausal breast cancer.

Publications

Excess weight gain accelerates 1-methyl-1-nitrosourea-induced mammary carcinogenesis in a rat model of premenopausal breast cancer.

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