Abstract 3601: Excess weight gain accelerates 1-methyl-1-nitrosourea (MNU)-induced mammary carcinogenesis in ovary-intact Sprague Dawley (Levin) rats fed 31.8% dietary calories from fat.
Authors: Matthews Shawna B. , McGinley John N. , Zhu Zongjian , Jiang Weiqin , Neil Elizabeth , Neil Angie , Thompson Henry J. 
Published: August 2014

Abstract
Though population data for breast cancer indicate that adult weight gain is associated with increased risk in postmenopausal women, the generally accepted lack of effect of obesity on premenopausal breast cancer risk has recently been challenged (Cecchini et al Cancer Prev Res; 5(4); 583-92, 2012). In that publication from the National Surgical Adjuvant Breast and Bowel Project (NSABP), BMI &gt;30 was significantly associated with increased risk of invasive breast cancer in high-risk premenopausal women (HR= 1.70). As the effects of excess weight gain on breast carcinogenesis in women prior to menopause remain poorly understood, the Levin strains of outbred Sprague Dawley rats that are dietary obesity sensitive (DS) or resistant (DR) were used to investigate this issue. The Levin rats, which are available from Taconic Farms, were selectively outbred for &gt;20 generations for resistance (DR) or susceptibility (DS) to weight gain when fed a purified diet of similar fat content as the typical diet consumed by women in the United States (31.8% fat by kcal). DS rats gain more weight than DR rats and develop metabolic syndrome after several weeks, including dyslipidemia and insulin resistance. Ovary-intact DS (n=101) and DR (n=103) rats were injected with 50 mg/kg of 1-methyl-1-nitrosourea (MNU) at 21-24 days of age, and began ad libitum feeding of the purified diet the following day. The experiment was terminated 9 weeks post-carcinogen at which point DS rats were approximately 17% heavier than their DR counterparts (220.3 ± 22.1 g vs. 187.9 ± 14.6 g, p&lt;0.0001). The incidence, multiplicity, and tumor burden per rat of histopathologically confirmed palpable mammary carcinomas were significantly higher in the DS versus DR rats (incidence 93.07% vs. 64.08%, p&lt;0.05; multiplicity, 4.17 tumors vs. 1.82 tumors, p&lt;0.01; tumor burden, 7.42 g vs. 1.93 g, p&lt;0.0001) and cancer latency was reduced (37.9 ± 9.0 days vs. 44.0 ± 6.7 days, p&lt;0.0001). Molecular subtypes of tumors in DS and DR are currently being evaluated. These results suggest that the Levin model of DS and DR rats represents a valuable preclinical tool for further investigating how excessive energy intake and weight gain with accompanying metabolic syndrome affect the carcinogenic process in the breast.
Supported by PHS grant CA52626 from the National Cancer Institute.
Citation Format: Shawna B. Matthews, John N. McGinley, Zongjian Zhu, Weiqin Jiang, Elizabeth Neil, Angie Neil, Henry J. Thompson. Excess weight gain accelerates 1-methyl-1-nitrosourea (MNU)-induced mammary carcinogenesis in ovary-intact Sprague Dawley (Levin) rats fed 31.8% dietary calories from fat. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3601. doi:10.1158/1538-7445.AM2013-3601