Extranuclear signaling by estrogen: Role in breast cancer progression and metastasis

The estrogen receptor (ERα) is implicated in the progression of breast cancer. Hormonal therapies which block ER functions or local and systemic estrogen production are currently used to treat ERα positive breast cancer. Hormonal therapy shows beneficial effects, however, initial or acquired resistance to endocrine therapies frequently occurs, and tumors recur as metastasis. Emerging evidence suggests in addition to exerting its well-studied nuclear functions, ERa also participates in extranuclear signaling that involve growth factor signaling components, adaptor molecules and the stimulation of cytosolic kinases. ERα extranuclear pathways have the potential to activate gene transcription, modulate cytoskeleton, and promote tumor cell proliferation, survival, and metastasis. Cytoplasmic/membrane ERα is detected in a subset of breast tumors and expression of extranuclear components ERα is deregulated in tumors. The extranuclear actions of ER are emerging as important targets for tumorigenic and metastatic control. Inhibition of ERα extranuclear actions has the potential to prevent breast tumor progression and may be useful in preventing ERα positive metastasis. In this review, we summarize the results of recent research into the role of ERα mediated extranuclear actions in breast tumorigenesis and metastasis.