ER-α36: a novel biomarker and potential therapeutic target in breast cancer

Estrogen receptor-alpha36 (ER-alpha 36) is a 36-kDa variant of estrogen receptor-alpha (ER-alpha) firstly identified and cloned by Wang et al in 2005. It lacks both transactivation domains (activation function 1 and activation function 2) and has different biological characteristics compared to traditional ER-alpha (ER-alpha 66). ER-alpha 36 primarily locates on plasma membrane and cytoplasm and functions as a mediator in the rapid membrane-initiated non-genomic signaling pathway. Additionally, it inhibits the traditional genomic signaling pathway mediated by ER-alpha 66 in a dominant-negative pattern. Accumulating evidence has demonstrated that ER-alpha 36 regulates the physiological function of various tissues. Thus, dysregulation of ER-alpha 36 is closely associated with plenty of diseases including cancers. ER-alpha 36 is recognized as a molecular abnormality which solidly correlates to carcinogenesis, aggressiveness, and therapeutic response of breast cancer. Additionally, special attention has been paid to the role of ER-alpha 36 in endocrine therapy resistance. Therefore, ER-alpha 36 provides a novel biomarker of great value for diagnosis, prognosis, and treatment of breast cancer. It may also be a potential therapeutic target for breast cancer patients, especially for those who are resistant to endocrine therapy. In this review, we will overview and update the biological characteristics, underlying mechanism, and function of ER-alpha 36, focusing on its biological function in breast cancer and endocrine therapy resistance. We will evaluate its application value in clinical practice.