METHYLATION OF ESTROGEN AND PROGESTERONE-RECEPTOR GENE 5'-CPG ISLANDSCORRELATES WITH LACK OF ESTROGEN AND PROGESTERONE-RECEPTOR GENE-EXPRESSION IN BREAST-TUMORS

Hormonal factors have a profound influence on the development, treatme nt, and outcome of breast cancer, The absence of steroid hormone recep tors is highly correlated with resistance to antihormonal treatments, Work in cultured human breast cancer cell lines has shown that the abs ence of estrogen receptor (ER) gene expression in ER-cells is associat ed with extensive methylation of the ER gene 5' CpG island, and treatm ent with agents that demethylate the ER gene CpG island results in the production of functional ER protein, The current study shows that CpG islands in the 5' region of the ER and progesterone receptor (PR) gen es are methylated in a significant fraction of primary human breast ca ncer tissues, The ER CpG island is methylated at the methylation-sensi tive NotI restriction site in 9 of 39 (25%) of primary ER- breast canc ers but remains unmethylated in 53 ER+ breast cancers and 9 normal bre ast specimens. Three methylation-sensitive restriction sites in the PR gene CpG island are not methylated in normal breast specimens and PR human breast cancers but are hypermethylated in 40% of PR- human brea st tumors, These data demonstrate that methylation of the ER and PR ge ne CPG islands is associated with the lack of ER and PR gene expressio n in a significant fraction of human breast cancers.