Estrogen Receptor

To many, progression of breast cancer and loss of estrogen receptor (ER) are synonymous. The perception is that normal breast tissue is ER*, is growth stimulated by estrogen, and is dependent upon estrogen for growth. Patients with ER⁺ invasive carcinoma have better prognosis than those with ER-negative cancer. Furthermore, loss of receptor makes the cancer more difficult to treat because hormonal manipulation is not useful. However, in the normal breast very few epithelial cells are ER⁺.

The number varies with the menstrual cycle but by immunohistochemical methods they are fewer than 10% of the normal epithelial cell population (Petersen et al., 1987; Jacquemier et al., 1990). Expression of ER increases in benign breast lesions.

Immunohistochemical analysis of ER expression in biopsy specimens from premenopausal patients found 6% of normal cells positive, 12% of epithelial cells in fibroadenomas, 13% in atypical lobular hyperplasia, and 31% in CIS (Jacquemier et al., 1990). However, in postmenopausal cases, 26% of normal cells, 25% of fibroadenoma cells, 73% of epithelial cells from proliferative lesions, and 30% from DCIS were positive.

In a case control study in which ER⁺ status of benign lesions was defined as the presence of any nuclear staining, 84% of cases versus 57% of controls were ER⁺ (Khan et al., 1994). Progesterone receptor status was similar-86% positive for both. The benign lesions were not further defined but the adjusted odds ratio for ER+ benign lesions in this study was 6.5 (Khan et al., 1994). In a study of 140 benign breast lesions of various types, including fibroadenomas, papillomas, and ductal hyperplasias, 70% showed some nuclear staining (Giri et al., 1989).

Many immunohistochemical studies use the H score system which multiplies the % of cells positive by the intensity of staining (1⁺, 2⁺, or 3⁺) for each positive cell.

Thus, the maximum score is 300 (all cells 3⁺). Using an H score of 20 as the criterion for classification as ER⁺, Schmitt (1995) found that the proportion of positive cases was similar for PBD and breast cancer, but proliferation indices, determined by MIB-1 antibody staining, were higher in ER⁺ than in ER-negative hyperplastic lesions. On the other hand, MIB-1 staining of DCIS and invasive cancer cases was greater in ER-negative than in ER⁺ cases, suggesting alteration in mitogenic response to estrogen with progression rather than alteration of receptor expression (Schmitt, 1995). However, due to the low H score used in this study, 80% of normal biopsies were also judged to be positive.

It has been reported that at least 25% of the epithelial nuclei stain strongly in 30% of benign breast lesions (Giri et al., 1989). This level of staining corresponds to biochemical assay values in excess of 10 fmol/mg protein (Giri et al., 1987), a level frequently used clinically as the cut off for classifying cancer as ER positive or negative.