Derailed Estrogen Signaling and Breast Cancer: An Authentic Couple

Estrogen or 17 beta-estradiol, a steroid hormone, plays a critical role in the development of mammary gland via acting through specific receptors. In particular, estrogen receptor-alpha (ER alpha) acts as a transcription factor and/or a signal transducer while participating in the development of mammary gland and breast cancer. Accumulating evidence suggests that the transcriptional activity of ER alpha is altered by the action of nuclear receptor coregulators and might be responsible, at least in part, for the development of breast cancer. In addition, this process is driven by various posttranslational modifications of ER alpha, implicating active participation of the upstream receptor modifying enzymes in breast cancer progression. Emerging studies suggest that the biological outcome of breast cancer cells is also influenced by the cross talk between microRNA and ER alpha signaling, as well as by breast cancer stem cells. Thus, multiple regulatory controls of ER alpha render mammary epithelium at risk for transformation upon deregulation of normal homeostasis. Given the importance that ER alpha signaling has in breast cancer development, here we will highlight how the activity of ER alpha is controlled by various regulators in a spatial and temporal manner, impacting the progression of the disease. We will also discuss the possible therapeutic value of ER alpha modulators as alternative drug targets to retard the progression of breast cancer. (Endocrine Reviews 34: 1-32, 2013)