Impact of Obesity on Tamoxifen Chemoprevention in a Model of Ductal Carcinoma in Situ
Abstract
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; n=90/genotype) were randomized (30/group) to receive: control diet (modified AIN-76A); a 30% CR regimen (isonutrient); or a DIO regimen. A subset of mice (n=4 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).
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2012
- Accession Number
- ADA581256
Entities
People
- Sarah M. Smith
Organizations
- University of Texas at Austin