The expression of
estrogen receptor-alpha (ER-alpha) and related genes has emerged as one of the major determinants of molecular classification of invasive breast
cancers. Expression of a second ER,
estrogen receptor-beta (ER-beta), has not been previously evaluated in a large population-based study. Therefore, we examined ER-beta expression in a large population of women with
breast cancer to assess its relationship to molecular categories of invasive
breast cancer. We constructed tissue microarrays from
paraffin blocks of 3093 breast
cancers that developed in women enrolled in the Nurses' Health Study. Tissue microarray sections were immunostained for ER-alpha,
progesterone receptor (PR),
human epidermal growth factor receptor 2 (HER2),
cytokeratin 5/6,
epidermal growth factor receptor (EGFR) and with a
monoclonal antibody to ER-beta.
Cancers were categorized as
luminal A (ER-alpha+ and/or PR+ and HER2-);
luminal B (ER-alpha+ and/or PR+ and HER2+); HER2 (ER-alpha- and PR- and HER2+); and basal-like (ER-alpha-, PR-, HER2- and EGFR or
cytokeratin 5/6+). The relationship between expression of ER-beta and molecular class of invasive
breast cancer was analyzed. Overall, 68% of
breast carcinomas were ER-beta+. Expression of ER-beta was significantly associated with expression of ER-alpha (P<0.0001) and PR (P<0.0001), and was inversely related to expression of HER2 (P=0.004), CK5/6 (P=0.02) and EGFR (P=0.006). Among 2170 invasive
cancers with complete immunophenotypic data, 73% were
luminal A, 5%
luminal B, 6 % HER2 and 11% basal-like. ER-beta expression was significantly related to molecular category (P<0.0001) and was more common in
luminal A (72% of cases) and B (68% of cases) than in HER2 or basal-like types. However, despite their being defined by the absence of ER-alpha expression, 55% of HER2-type and 60% of basal-like
cancers showed expression of ER-beta. The role of ER-beta in the development and progression of breast
cancers defined by lack of expression of ER-alpha merits further investigation.