Estrogen receptors and proliferation markers in primary and recurrent breast cancer

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