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 observ ed in 48% of the spontaneous mammary tumors in old female Wistar rats and 2 2% of the contralateral normal mammary tissues. The majority of the methyla tion losses were total. Similarly, 50% of 7,12-dimethylbenz[a]anthracene (D MBA)-induced mammary tumors in young Sprague-Dawley rats exhibited a partia l or total loss of methylation at this site, while all normal mammary tissu es in young rats were fully methylated. Loss of ER methylation also increas ed 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 obta ined 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 ris k, in old than young, and in mammary tumors than in normal tissues. The dat a suggest that hypomethylation of a growth-associated ER gene may be a comm on event in mammary tumorigenesis in the rat and may be of predictive value as a marker of increased breast cancer risk in aged individuals. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.