Prognostic Significance of Estrogen Receptor Beta in Epithelial Hyperplasia of Usual Type With Known Outcome

Abstract

The prognostic significance of ER-alpha expression in benign proliferative breast disease has been confirmed in epithelial hyperplasia of usual type (HUT). However, little is known about the role of ER-beta in these lesions. Therefore, this study was performed to test the hypothesis that, in HUT lesions, the ratio of ER-alpha:ER-beta is an accurate determinant of breast cancer risk and of predicting subsequent progression to invasive breast cancer. This case-control study analyzed a cohort of benign proliferative breast lesions and foci of ductal HUT in 117 patients with long follow-up (20 years). These foci were analyzed by morphometric image analysis together with immunohistochemistry using monoclonal antibodies to ER-beta1 and to ER-alpha. The data were compared with ER-beta expression in all breast carcinomas that subsequently developed in the same patients as well as to ER-alpha expression in the corresponding tissues. In cases that progressed to carcinoma, the ratio of ER-alpha to ER-beta in HUT was significantly higher (P < 0.001) than in those that did not progress. None of the HUT foci from patients who progressed to breast cancer were simultaneously ER-alpha negative and ER-beta positive. Using both ER-beta and ER-alpha in a logistic model demonstrated a 75% correct classification rate for the cohort studied. These findings confirm the diagnostic and prognostic value of defining the ER-alpha and ER-beta status of HUT lesions identified morphologically. The data support the hypothesis that high ER-alpha:ER-beta levels characterize those cases within HUT likely to progress to breast cancer. The data also reveal that a reduced level of ER-beta relative to ER-alpha is an accurate predictor of individual cases of HUT likely to progress to invasive breast carcinoma, thus supporting the concept that ER-alpha transcriptional activity is directly modulated by ER-beta.

Nuclear and Cytoplasmic Expression of ERβ1, ERβ2, and ERβ5 Identifies Distinct Prognostic Outcome for Breast Cancer Patients

“…There are observational reports of cytoplasmic ERh immunoreactivity in breast cancer (6,7,20,34), and we have previously shown that cytoplasmic expression is related to neoplastic progression with a higher incidence in in situ/invasive carcinoma compared with normal breast/ benign intraductal proliferation (35). We have also shown herein that this staining is specific because it can be blocked by peptide competition, but until now this has not been formally examined.…”

Estrogen receptor α and β in uterine fibroids: a basis for altered estrogen responsiveness

“…In addition, ERa is considered to be a key player during progression of benign mammary proliferative disorders to invasive carcinomas. Recent evidence suggests, however, that a high ERa-to-ERb ratio rather than the level of ERa alone is what characterizes those cases of mammary hyperplasia of the usual type that are likely to progress to breast cancer (16). In fact, there is ample evidence that, although ERa expression is maintained in breast cancer compared with benign tumors or normal mammary tissue, ERb expression is decreased (31).…”

“…In line with this, 17b-E 2 (hereafter referred to as E 2 ) has been reported to promote the growth of immortalized mammary cells through ERa and inhibit it through ERb (15). In mammary hyperplasia of the usual type, it is the ERa-to-ERb ratio rather than the individual receptor amounts that reportedly is associated with the risk that this lesion will develop into invasive carcinoma (16). Work with ERa-positive breast cancer cells engineered to express increasing amounts of ERb has shown that, although ERb could regulate genes that are not targeted by ERa alone, it increasingly affected genes regulated by ERa as well, although nearly half of ERa target genes were not affected even when the level of ERb was set to be much higher than that of ERa (17).…”

Immunohistochemical expression of estrogen receptors alpha and beta in lobular neoplasia

“…Of notice, ER-beta seems to exhibit a pattern inverse to ER-alpha, declining during the progression from normal breast tissue to atypical ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma [15,18]. The ER-beta/ER-alpha ratio has emerged as an important risk factor; a low ER-beta/ER-alpha ratio seems to predict progression to carcinoma in nonatypical epithelial hyperplasia [19]. It is interesting to note that ER-beta gradual reduction has been reported to be more pronounced in invasive ductal than in invasive lobular carcinomas [20].…”