Estrogen receptors and proliferation markers in primary and recurrent breast cancer

Abstract

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 ERalpha, ERbeta and the proliferation markers Ki67 and cyclin A. In benign tumors, most epithelial cells contained ERbeta, but ERalpha was rare. In primary cancers, both ERalpha and ERbeta occurred in epithelial cells, the presence of ERbeta being associated with elevated expression of Ki67 and cyclin A, and ERalpha with decreased levels. Thus, the highest content of proliferation markers was seen in primary cancers that were ERalpha(-) ERbeta(+). Most Ki67-containing cells coexpressed ERbeta, but few showed ERalpha. In locally recurring cancers, ERalpha, ERbeta, and Ki67 were more highly expressed than in the corresponding primary tumors, and many cells containing ERbeta, but few with ERalpha, expressed Ki67. Surprisingly, ERbeta, but not ERalpha, 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 ERalpha, cancer cells that lack ERalpha but contain ERbeta and proliferation markers represent a novel population of apparently proliferating cells that probably are not targeted by the current antiestrogens. Thus, appropriate ERbeta-specific ligands, perhaps in combination with tamoxifen, may be useful in improving the treatment of breast cancers.

Figure 1

Expression of ERα, ERβ, Ki67, and cyclin A in breast fibroadenoma and invasive ductal cancer. In fibroadenomas, ERα is seen only in epithelial cells (A), whereas ERβ is expressed in both epithelium and stroma (B). There was little Ki67 or cyclin A expression (C and D). In invasive ductal cancers, four patterns of ER expression can be identified: ERα⁺ ERβ⁺ (E and F), ERα⁺ ERβ⁻ (I and J), ERα⁻ ERβ⁺ (M and N), and ERα⁻ ERβ⁻ (Q and R). Some Ki67- and cyclin A-containing cells appear in ERα⁺ ERβ⁺ specimens (G and H), but ERα⁻ ERβ⁺ cancers express much higher levels of these proliferation markers (O and P). In contrast, ERα⁺ ERβ⁻ and ERα⁻ ERβ⁻ tumors contain little Ki67 or cyclin A (K, L, S, and T). (Magnification: ×200.)

Figure 2

Colocalization of ERα, ERβ, and Ki67 in invasive ductal breast cancer. Most of the ERα⁺ cells also contain ERβ (A–C). In ERα-dominant specimens, there are few cells containing Ki67, none of which coexpress ERα (D–F). In ERβ-dominant specimens, many cells express Ki67, and almost all of these coexpress ERβ (G–I). In C, F, and I, yellow indicates colocalization. (Magnification: ×200.)

Figure 3

Comparison of primary and recurrent mammary cancer from the same patient in the expression and colocalization of Ki67 with either ERα (A–F) or ERβ (G–L). The levels of both ERα and Ki67 are higher in the recurrent cancer (D and E) than in the primary (A and B). Most of the ERα⁺ cells do not express Ki67, and only a few show coexpression (C and F, arrow). However, in both primary (G–I) and recurrent cancers (J–L), 71–85% of Ki67-positive cells also express ERβ (I and L, red). (Magnification: ×200.).