ESR2 and Familial prostate cancer: For example, loss of ESR1 transcription and ESR1 protein by promoter methylation, respectively, increased with progression of prostatic disease from BPH to low grade and to high grade cancer [44–46].Most reports on ESR2 expression concur, that levels decline in localized prostate cancer with increasing grade from prostatic intraepithelial neoplasia through low to high grade Gleason scores [47–50].The loss of ESR2 expression in organ confined prostate cancer has been shown to be epigenetically regulated by progressive hypermethylation of ESR2 promoter [46, 51].