The normal breast epithelium of women with breast cancer displays an aberrant response to estradiol

Breast epithelial response to estradiol may play an important role in breas t cancer etiology, We have examined the relationship between serum estradio l and progesterone levels and normal breast epithelial expression of estrog en receptor (ER) alpha, progesterone receptor (PgR), and epithelial prolife ration las reflected by the Ki-67 labeling index) in 121 women (50 newly di agnosed breast cancer cases and 71 benign breast disease controls), Simulta neous samples of grossly normal breast tissue and venous blood were obtaine d from women undergoing breast surgery. Serum estradiol and progesterone le vels were measured by radioimmunoassay; breast epithelial ER, PgR, and Ki-6 7 expression was measured by immunohistochemistry. Linear regression, contr olled for patient age and ductal and lobular composition of the tissue, sho wed that the breast epithelium of control women displayed an inverse correl ation between serum estradiol and ER-alpha, which was not seen in case wome n (P for the difference in regression slopes = 0.001), PgR expression displ ayed a significant positive correlation with serum estradiol in cases, but not in controls. Epithelial proliferation had no relationship to either est radiol or progesterone in both cases and controls but showed an inverse rel ationship with ER in controls and a direct relationship in cases (P for the difference in regression slopes = 0.066). These results suggest a dysregul ation of hormonal response in the normal breast epithelium of high-risk wom en, with lack of regulation of ER by estradiol, increased estrogen responsi veness as reflected by PgR expression, and a dissociation of ER expression and proliferative response.