Expression pattern and methylation of estrogen receptor α in breast intraductal proliferative lesions

Intraductal proliferative lesions of the breast including usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are associated with increased risk, albeit of greatly different magnitudes, for the subsequent development of invasive carcinoma. Estrogen receptor alpha (ER alpha) has been widely accepted as a prognostic marker and a predictor for endocrine therapy response of breast cancer. To investigate the ER alpha expression and methylation in breast intraductal proliferative lesions, we analyzed ER alpha expression in breast intraductal proliferative lesions including pure UDH (N=98), ADH without DCIS (N=160), DCIS without invasive breast cancer (N=149) by immunohistochemistry. Furthermore, the methylation status of ER alpha by methylation-specific PCR (MSP) was defined in 217 cases of breast intraductal proliferative lesions. Immunohistochemistry showed that 98/98 (100%) of the UDH cases were positive for ER alpha expression. ER alpha protein expression in ADH (132/160) (92.5%) was higher than in DCIS (101/149) (67.8%). But the ER alpha expression pattern was different with histological diversity of breast intraductal proliferative lesions. The average percent cells staining positive for ER alpha was 35.33% in UDH, 87.75% in ADH and 71.45% in DCIS. ER alpha methylation in 32/60 (53.3%) UDH, 11/77 (10.2%) ADH and 32/80 (40.0%) DCIS. Our results demonstrated a strong negative correlation between the percent of cells staining positive for ER alpha and ERa methylation (r=-0.831, p<0.001). Taken together, our results underlined that ER alpha expression or methylation may be involved in the breast carcinogenesis and advancement, thus it is not parallel to breast cancer risk in breast intraductal proliferative lesions. No obvious watershed between ER alpha-positive and-negative breast carcinogenesis was established. Estrogen receptor (ER) methylation or expression is a reversible signal in breast carcinogenesis which affected biological behavior of cells.