Abstract 5367: Comparison of global DNA methylation in uterine tissue from different species of monkeys and humans exposed to tamoxifen.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Tamoxifen (TAM) is a selective estrogen receptor modulator used worldwide for adjuvant therapy and chemoprevention of breast cancer. However, women receiving TAM therapy have an increased risk of endometrial and myometrial cancer, which may be due to genotoxicity and/or estrogen receptor-related mechanisms. It is now accepted that cancer can be both a genetic and an epigenetic disease, with these components participating at all stages of cancer development. DNA methylation at the 5-position of cytosine silences gene expression. Aberrant global DNA 5-methylcytosine (5-mC) levels may produce critical changes in the expression of genes that regulate cell growth and invasiveness. In order to study the effect of TAM exposure on uterine 5-mC levels, we examined uterine tissues taken from aging Erythrocebus patas (patas) and Macaca fascicularis (macaque) monkeys given oral TAM dosing for 3-4 months. In addition, we evaluated endometrial and myometrial samples from breast cancer survivors, who typically receive adjuvant TAM therapy for 5 years. The percentage of 5-mC in DNA was determined by an ELISA that employed a highly-specific 5-mC antibody. Of 5 female patas, 2 were unexposed and 3 were given oral dosing with 1.7 mg TAM/kg bw/day for 3 months. Of 12 female macaques, 6 were unexposed and 6 were given 1.3 mg TAM/kg bw/day for 4 months. Also, uterine tissue was taken at surgery or autopsy from normal-appearing areas and malignant-appearing areas, from women who received 20 mg TAM/day (n=9) and unexposed women (n=6). The patas monkeys given TAM had significantly increased levels of uterine 5-mC compared to the controls (2.9±0.13% vs. 1.9±0.26%, mean ± SE, respectively, p=0.03). However, the macaques showed no significant differences in uterine 5-mC between unexposed and TAM-exposed animals (0.93%±0.1 vs. 1.07%±0.05, mean ± SE, respectively). In human patients, TAM treatment did not alter the global 5-mC levels in either normal-appearing or malignant-appearing endometrium. However, global 5-mC levels in normal-appearing endometrium from the combined TAM-treated and untreated women (n=6) were significantly lower than those found in malignant-appearing uterine tissue from the combined TAM-treated and untreated (n=9) group (0.33%±0.01 vs. 0.70%±0.09, mean ± SE, respectively, p=0.006). Therefore, changes in uterine global DNA 5-mC are not altered consistently within primate species as a result of long-term TAM exposure, suggesting that 5-mC alterations are not major contributors to TAM-induced endometrial cancer. Continuing studies will evaluate 5-mC levels in the promoter regions of specific genes that are modulated in expression level during TAM therapy. Citation Format: Elena E. Hernandez Ramon, Nancy Si, Mark J. Cline, Charles E. Wood, Ruth Woodward, Miriam C. Poirier. Comparison of global DNA methylation in uterine tissue from different species of monkeys and humans exposed to tamoxifen. [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 5367. doi:10.1158/1538-7445.AM2013-5367