Background: Obesity is associated with increased breast cancer mortality in premenopausal women, who predominately develop estrogen receptor (ER)-α negative breast tumors. New mechanism-based targets and intervention strategies for offsetting the procancer effects of obesity are urgently needed given the rising rates of obesity in women throughout the world and the lack of effective targeted therapies for ER-negative breast cancer. Unfortunately, the mechanisms by which obesity impacts ER-negative breast cancer prognosis remain unclear.

Methods: In this study, we utilized the MMTV-neu transgenic mouse model of Her2+ breast cancer to test the hypothesis that dietary energy balance modulation alters mammary tumor development and progression through epigenetic regulation of ER in the mammary epithelium of these mice. MMTV-neu transgenic mice form spontaneous mammary tumors that progress from an ERα-positive hyperplasia to aggressive ERα-negative ductal adenocarcinomas. Female MMTV-neu transgenic mice were randomized to 3 diet regimens (30/regimen), resulting in either an obese, overweight or lean phenotype. A subset of mice were killed at baseline, 1, 3, and 5 months following diet initiation, and tissues were collected for analysis; remaining animals were followed for up to a 22 month survival study.

Results: Gene and protein expression analysis revealed that mammary ERα expression, known to be lost by 8 weeks of age in normoweight MMTV-neu transgenic mice, was maintained in lean mice but lost in the overweight and obese mice (which did not statistically differ in any parameter studied). Additionally, we found lean mice had significantly increased mammary ERβ gene expression and delayed onset of hyperplasia relative to the overweight/obese mice. ERα and ERβ gene intron methylation increased from 5 months to 12 months on diet in lean mice and conversely decreased in overweight/obese mice, which parallels the ER gene expression data. After 22 months of feeding, lean mice had significantly increased tumor-free survival in relative to the overweight/obese mice. Interestingly, human and mouse HER2+ (but not but not HER2-) breast cancer cell lines, when treated with serum from obese (BMI>30), women resulted in a significant down-regulation of ERβ gene expression.

Conclusions: In MMTV-neu transgenic mice, dietary energy balance modulation impacts spontaneous mammary tumor development and ERα and ERβ levels in normal and tumor tissue, possibly through epigenetic mechanisms. Moreover, increased mammary ERβ expression may represent a novel target for interventions to offset the enhancing effects of obesity on breast cancer.

Citation Format: Emily L. Rossi, Sarah M. Dunlap, Nikki A. Ford, Laura W. Bowers, Stephen D. Hursting. Maintenance of a lean phenotype is associated with increased ERβ expression and ERβ gene intron methylation in murine MMTVneu luminal mammary cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B29.