ESR1 and breast cancer: While deletions, insertions, rearrangements, or polymorphisms of the ER-α gene are uncommon and are not generally associated with loss of ER-α,14, 15 there is increasing evidence that ER-α deficiency is a result of CpG island hypermethylation within the ER-α promoter.16, 17, 18, 19 An abnormal methylation pattern can account for the transcriptional inactivation of the ER-α gene and consequent antiestrogen resistance in breast cancer cell lines and tumors.