Abstract P4-15-02: Investigating the use estrogen receptor β agonists in the prevention of breast cancer using a transgenic mouse model

Abstract

Abstract Breast cancer is the most common cancer among women worldwide. In the United States, 1 in 8 women will develop breast cancer during her lifetime, and in 2016 over 240,000 new cases will be diagnosed. Incidence rates differ by geographic location, with women living in Asia having the lowest rates. However, after migrating to the U.S and adopting a western diet their rates increase. This highlights the importance of lifestyle, including diet, in modulating breast cancer risk. Soy has been previously implicated as the dietary component contributing to the reduced breast cancer rates in Asian women. Compounds that can selectively activate Estrogen Receptor β have been identified in plants, including soy. Given the tumor-suppressive properties of ERβ, it may be possible to use these agonists in the chemoprevention of breast cancer. The objective of this study was to investigate the utility of using ERβ agonists in the prevention of breast cancer using a transgenic mouse model. MMTV-HER2/neu mice develop premalignant lesions at 4-5 months, and tumors starting at month 7 due to overexpression of the Her2/neu proto-oncogene. MMTV-HER2/neu mice were treated with 2 different ERβ agonists, S-equol or LY500307, for 3 months and evaluated for branching, hyperplasia and differential gene expression. When compared to controls, ERβ agonist-treated mice exhibited a significant decrease in branching and ductal hyperplasia, with no change in body weight. Differential gene expression analysis revealed 218 modified genes in response to S-equol treatment, and 258 genes modified by LY500307 treatment, with an overlap of 36 genes. Pathway analysis identified an enrichment for chemokines signaling pathways, particularly TNF, in the reversal of hyperbranching resulting from treatment with ERβ agonists. Although previous studies have demonstrated crosstalk between ER's non-genomic signaling and growth factor signal transductions pathway, this is the first study to demonstrate the impact of ERβ activation on HER2/neu mediated pre-neoplastic changes. Our study suggest that ER β agonist treatment may be a valuable therapeutic option for the chemoprevention of breast cancer in women at increased risk. Citation Format: Samayoa C, Krishnegowda NK, Vadlamudi RK, Tekmal RR. Investigating the use estrogen receptor β agonists in the prevention of breast cancer using a transgenic mouse model [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-15-02.