Metastatic breast cancer is a life-threatening stage of cancer and is the leading cause of death in advanced breast cancer patients. Estrogen signaling and the estrogen receptor (ER) are implicated in breast cancer progression, and the majority of the human breast cancers start out as estrogen dependent. Accumulating evidence suggests that ER signaling is complex, involving coregulatory proteins and extranuclear actions. ER-coregualtory proteins are tightly regulated under normal conditions with miss expression primarily reported in cancer. Deregulation of ER coregualtors or ER extranuclear signaling has potential to promote metastasis in ER-positive breast cancer cells. This review summarizes the emerging role of ER signaling in promoting metastasis of breast cancer cells, discusses the molecular mechanisms by which ER signaling contributes to metastasis, and explores possible therapeutic targets to block ER-driven metastasis. 1. Introduction The steroid hormone, estradiol, plays an important role in the progression of breast cancer, and a majority of the human breast cancers start out as estrogen dependent and express the estrogen receptor (ER). The biological effects of estrogen are mediated by its binding to one of the structurally and functionally distinct ERs (ERα and ERβ) [1]. Endocrine therapy using Tamoxifen, a selective estrogen receptor modulator [2], and aromatase inhibitors, which ablate peripheral estrogen synthesis, has been shown to substantially improve disease-free survival [3]. Endocrine therapy has also been shown to have a positive effect on the treatment of ER-positive breast cancer [4]. Despite these positive effects, initial or acquired resistance to endocrine therapies frequently occurs with tumors recurring as metastatic. Tumor metastasis comprises a series of discrete biological processes that moves tumor cells from the primary neoplasm to a distant location [5] and involves a multi-step cascade of coordinated cell adhesion and contractility as well as proteolytic remodeling of the extracellular matrix (ECM) [6, 7]. Even though substantial information is available on the process of metastasis, the molecular basis of breast cancer progression to metastasis and the role of ERα signaling in this process remain poorly understood. A few early studies suggested a negative effect of ERα signaling on motility and invasion of cells [8, 9], while several recent studies showed a positive effect of ER signaling on motility [10–14]. In this review, we summarized the emerging evidence for the role of ERα signaling in breast cancer
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