The estrogen / estrogen receptor (ER) signaling is implicated in breast cancer progression. The majority of human breast cancers start out as ER positive and a large portion of metastases retain their ER. While initial endocrine therapy has a positive effect on the treatment of advanced metastatic disease, acquired resistance to endocrine therapies frequently occurs, with tumors recurring as metastases, which is the leading cause of death from breast cancer. The molecular basis of breast cancer progression to metastasis and the role of ER signaling in this process remain poorly understood. Emerging evidence suggests that ER participates in extra-nuclear signaling in addition to genomic functions. This study hypothesized that deregulation of ER extra-nuclear signaling lead to cell migration and metastasis. Using various biochemical approaches, this study demonstrated that ER extra-nuclear actions enhance cytoskeleton structures in cancer cells that play a key role in cell motility. Utilizing xenografts of human tumors grown in immunodeficient mice, this study found that ER extra-nuclear actions contribute to cell migration and tumor cell motility and that targeting the ER extra-nuclear actions represents a novel therapeutic target to combat breast cancer progression to metastasis in ER-positive breast tumors. Further, this study also tested the ability of FDA approved drug Dasatinib to block estrogen mediated extra-nuclear signaling and cell migration functions. In summary, this data provide the first evidence demonstrating the significance of ER extra-nuclear signaling to the metastatic potential of breast cancer cells and thus represent a novel target to prevent the emergence of ER-positive metastatic cells via blockage of ER extra-nuclear signals in combination with endocrine therapy.
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