ERβ in normal and malignant breast

We have shown that in the rodent mammary gland ERβ is the dominant ER, and that, in response to E2, ERα but not ERβ is downregulated in the early G1 phase of the cell cycle. Cells that contain ERα receive the signal to proliferate from E2, and within 4 hours of that signal ERα is lost from the nucleus. The cells then go through a complete cycle and ERα reappears in daughter cells. ERβ levels do not change in cell nuclei during the cell cycle. This pattern of ER regulation holds true in human breast cancer since ERα is never co-localized with proliferation markers in breast cancer samples. This means that under the conditions of a constant high level of E2, ERα does not reappear in the nucleus. A similar situation exists during pregnancy when there is a constant high level of E2 and there is no ERα in the mammary epithelium. This resistance to the proliferative response to E2 in the presence of a constant high dose of E2 probably explains the very successful use of high-dose E2 in the treatment of breast cancer. ERβ, on the other hand, appears to have a differentiative role not a proliferative role in the mammary gland, and the lactating rodent mammary gland of ERβ-/- mice does not express gap junction and adhesion proteins, typical indicators of fully differentiated cells.In recent years there have been several publications showing that ERβ is expressed in human breast cancer, and conclusions and speculations about a causative role for ERβ in breast cancer development and/or progression have been made. We have studied 500 frozen breast biopsies in collaboration with Prof. RC Coombes, London, in order to clarify the role of ERβ in normal and malignant breast. In this study we measured ERα and ERβ proteins by several techniques (immunohistochemistry, western blotting, ligand binding in sucrose gradients, and RT-PCR) in various human samples obtained from both benign breast and malignant breast. We found that ERβ is the predominant estrogen receptor in the normal mamma