Hypomethylation of an exon I estrogen receptor CpG island in spontaneous and carcinogen induced mammary tumorigenesis in the rat

Loss of methylation at a CpG island in exon I of the rat ER gene was observed in 48% of the spontaneous mammary tumors in old female Wistar rats and 22% of the contralateral normal mammary tissues. The majority of the methylation losses were total. Similarly, 50% of 7,12- dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in young Sprague- Dawley rats exhibited a partial or total loss of methylation at this site, while all normal mammary tissues in young rats were fully methylated. Loss of ER methylation also increased with age in normal mammary tissues of tumor- free rats approaching 12.5% in middle-aged and 43% in old rats. In addition, 66% of mammary glands obtained from young rats that are subsequently at an increased risk to develop breast cancer due to manipulation of in utero dietary fat intake, exhibited methylation loss while no methylation changes were observed in rats at no increased risk for breast cancer. Therefore, the loss of ER methylation is more extensive in mammary glands of rats at high than low breast cancer risk, in old than young, and in mammary tumors than in normal tissues. The data suggest that hypomethylation of a growth-associated ER gene may be a common event in mammary tumorigenesis in the rat and may be of predictive value as a marker of increased breast cancer risk in aged individuals.