Estrogen receptors and proliferation markers in primary and recurrent breast cancer

To elucidate the clinical importance of estrogen receptor (ER) β in breast cancer, 29 archival primary breast cancer specimens, six locally recurrent cancers, and five benign mammary tumors were examined histochemically for ERα, ERβ and the proliferation markers Ki67 and cyclin A. In benign tumors, most epithelial cells contained ERβ, but ERα was rare. In primary cancers, both ERα and ERβ occurred in epithelial cells, the presence of ERβ being associated with elevated expression of Ki67 and cyclin A, and ERα with decreased levels. Thus, the highest content of proliferation markers was seen in primary cancers that were ERα(−) ERβ(+). Most Ki67-containing cells coexpressed ERβ, but few showed ERα. In locally recurring cancers, ERα, ERβ, and Ki67 were more highly expressed than in the corresponding primary tumors, and many cells containing ERβ, but few with ERα, expressed Ki67. Surprisingly, ERβ, but not ERα, was seen in the stromal cells of both primary and recurrent cancers. Because the response of breast cancers to tamoxifen therapy is correlated with the presence of ERα, cancer cells that lack ERα but contain ERβ and proliferation markers represent a novel population of apparently proliferating cells that probably are not targeted by the current antiestrogens. Thus, appropriate ERβ-specific ligands, perhaps in combination with tamoxifen, may be useful in improving the treatment of breast cancers.