ERβ in normal and malignant breast

Abstract

Both ERα and ERβ are expressed in not only normal breast of the rodent, cow, monkey and human, but also in breast cancer. Cells that express ERα are found within the luminal epithelium, but not in the myoepithelium or stroma in the human breast. ERβ, on the other hand, is expressed not only in the luminal epithelial cells, but also in myoepithelial cells, stromal cells and in passenger lymphocytes. This widespread distribution of ERβ suggests multiple roles for ERβ in the mammary gland. 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 mammary gland and in benign breast disease. There is very little ERα in the normal mammary gland. This low expression of ERα is one of the striking differences between rodents and humans. This is in stark contrast to ERβ, which is expressed in 80% of epithelial cells and is also present in the stroma. We found that ERα is abundantly expressed in invasive and in situ ductal carcinoma but not in medullary cancer. ERβ is also expressed in breast cancer, both ductal and medullary. In this study we also found that, in the human breast, the major ER in breast stroma is ERβ. This surprising finding has necessitated several new lines of investigation about the function of ERβ in the breast. It has long been thought that ERα in the stroma was responsible for secretion of growth factors in response to E2 and that these growth factors were responsible for epithelial cell proliferation. The discovery that it is ERβ that is present in the stroma might suggest a role of ERβ in growth factor secretion.