Abstract. Ezrin, previously also known as cytovillin, p81, and 80K, is a cytoplasmic protein enriched in microvilli and other cell surface structures. Ezrin is postulated to have a membrane-cytoskeleton linker role. Recent findings have also revealed that the NH:-terminal domain of ezrin is associated with the plasma membrane and the COOH-terminal domain with the cytoskeleton (Algrain, M., O. Turunen, A. Vaheri, D. Louvard, and M. Arpin. 1993. J. Cell Biol. 120: 129-139). Using bacterially expressed fragments of ezrin we now demonstrate that ezrin has an actinbinding capability. We used glutathione-S-transferase fusion proteins of truncated ezrin in affinity chromatography to bind actin from the cell extract or purified rabbit muscle actin. We detected a binding site for filamentous actin that was localized to the COOHterminal 34 amino acids of ezrin. No binding of monomeric actin was detected in the assay. The region corresponding to the COOH-terminal actin-binding site in ezrin is highly conserved in moesin, actincapping protein radixin and EM10 protein of E. multilocularis, but not in merlin/schwannomin. Consequently, this site is a potential actin-binding site also in the other members of the protein family. Furthermore, the actin-binding site in ezrin shows sequence homology to the actin-binding site in the COOH terminus of the B subunit of the actin-capping protein CapZ and one of the potential actin-binding sites in myosin heavy chain. The actin-binding capability of ezrin supports its proposed role as a membranecytoskeleton linker.

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

Estrogen is essential for normal growth and differentiation in the mammary gland. It also supports growth of approximately 50% of primary breast cancers. For this reason, removal of estrogen or blocking of its action with the anti-estrogen, tamoxifen, is the main treatment for estrogen receptor alpha (ERα)-positive tumors. In 1996, when oncologists became aware of a second ER, ERβ, there was some doubt as to whether this receptor would be of importance in breast cancer because the clinical consensus was that responsiveness to tamoxifen is related to the presence of ERα in breast cancer. Today we know that ERα and ERβ have distinct cellular distributions, regulate separate sets of genes and can oppose each other's actions on some genes. We also know that ERβ is widely expressed in both the normal and malignant breast and that there are proliferating cells in the breast which express ERβ. In this review we summarize what is known about ERβ in breast cancer and examine the possibility that ERβ-selective ligands may well represent a useful class of pharmacological tools with a novel target, namely proliferating cells expressing ERβ.

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