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Impact of Obesity on Tamoxifen Chemoprevention in a Model of Ductal Carcinoma in Situ

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Annual rept. 15 Sep 2009 - 14 Sep 2012

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Obesity increases postmenopausal breast cancer risk and increases mortality in pre- and postmenopausal women. While the majority of breast cancers in obese women are estrogen receptor ERalpha-positive, ERalpha-negative tumors confer a much worse prognosis. The mechanism by which obesity affects ER-negative breast cancer risk and prognosis is not clear, and strategies for offsetting the negative effects of obesity are urgently needed. In this study, we utilized the MMTV-neu mouse model of luminal-type breast cancer to test the hypothesis that energy balance modulation, through diet-induced obesity DIO or calorie restriction CR regimens, alters mammary tumor development and progression through regulation of ER in the mammary epithelium. MMTV-neu mice form spontaneous mammary tumors that progress from an ERalpha-positive hyperplasia to aggressive ERalpha-negative ductal adenocarcinomas. Female MMTV-neu transgenic mice and non-transgenic host strain FVB mice 6-8 weeks old n90genotype were randomized 30group to receive control diet modified AIN-76A a 30 CR regimen isonutrient or a DIO regimen. A subset of mice n4 per group was killed at 1, 3, and 5 months following diet initiation, and tissues were collected for analysis remaining animals were followed for a 60-week survival study. We found that, relative to control diet, the DIO regimen significantly increased body weight, percent body fat p is less than 0.0001, and obesity associated serum hormones and growth factors IGF-I, insulin, leptin, and estradiol p is less than 0.01 for all in both MMTV-neu and FVB controls. Conversely, CR significantly decreased body weight, percent body fat p is less than 0.0001 and decreased serum hormones growth factors, while increasing adiponectin each at p is less than 0.01.

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  • Biochemistry
  • Anatomy and Physiology
  • Medicine and Medical Research

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