The Role of Estrogen Receptor-β in Breast Cancer

Leigh C. Murphy, Ph.D.; Etienne Leygue, Ph.D.


Semin Reprod Med. 2012;30(1):5-13. 

In This Article

Abstract and Introduction


The discovery of a second estrogen receptor (ER), ERβ, has led to a reevaluation of estrogen action. The widespread expression of ERβ-like proteins in normal and neoplastic mammary tissues suggests a role of ERβ in the breast. Little progress has been made in elucidating this role or roles, but the presence of two ERs and variant isoforms in breast cancers presents challenges and opportunities to tease out complexities in understanding the estrogen signaling pathway in breast tissues. Identification of two groups of ERβ-expressing tumors in vivo, and the possibility of differential function, has already raised expectations that targeting ERβ may offer new treatment options for breast cancer patients where previously only aggressive chemotherapies were available. This supports continued efforts to understand the nature and function of ERβ in breast cancer, but it also suggests that ER status may need to be redefined to include an assessment of ERβ isoforms in addition to ERα.


The estrogen receptor (ER) is central to the biology of most human breast cancer. As such, ER has been and continues to be the target for the treatment and prevention of breast cancer. However, the ER is no longer a stand-alone molecule associated with a linear signaling pathway. ER signaling is now known to be remarkably complex and multifaceted. In particular, the discovery of a second ER, called ERβ, has been instrumental in a reevaluation of estrogen action in all tissues, either normal or neoplastic. Gene knockout studies clearly identify ERα expression as essential for normal mammary gland development. ERα today remains the primary target for endocrine therapies in breast cancer. As such, its levels are measured to determine the ER status of primary tumors and to predict the likelihood of patients responding positively to tamoxifen treatment, for example. Such data, in addition to >30 years of discovery and clinical experimentation, have established a central role of ERα in both normal and neoplastic mammary growth. In contrast, although 15 years have passed since the discovery of ERβ, the significance of its expression and its potential roles in normal mammary development, breast tumorigenesis, or tumor progression remain controversial and unclear. This article reviews the current research focused on elucidating the role of ERβ in breast cancer.


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