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in breast cancer
Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22903, USA
(Requests for offprints should be addressed to R X-D Song who is now at Division of Endocrinology, University of Virginia Health Science Center, Charlottesville, Virginia 22903, USA; Email: rs5wf{at}virginia.edu)
This paper was presented at the 2nd Tenovus/AstraZeneca Workshop, Cardiff (2006). AstraZeneca supported the meeting and the Welsh School of Pharmacy, Cardiff University has supported the publication of these proceedings.
Our recent studies have examined the role of various receptor complexes in the mediation of rapid, extranuclear effects of estradiol. This review describes 17ß-estradiol (E2)-initiated extranuclear signaling pathways, which involve the insulin-like growth factor 1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) and result in the activation of several kinase cascades. The biologic results of these effects are the enhancement of cell proliferation and diminution of programmed cell death (apoptosis). Until recently, most studies assigned priority to the nuclear transcriptional actions of estrogen receptor
(ER). Present investigative emphasis focuses on the additional importance of ER residing in or near the plasma membrane. A small fraction of ER is associated with the cell membrane and mediates the rapid effects of E2. Unlike classical growth factor receptors, such as IGF-1R and EGFR, ER has no transmembrane and kinase domains and is known to initiate E2 rapid signals by forming protein/protein complexes with many signaling molecules. Our recent studies demonstrate that the IGF-1R is involved in tethering ER to the plasma membrane, in activating the EGFR, and in the initiation of mitogen-activated protein kinase and phosphoinositide 3-kinase signaling. The formation of a multi-protein complex containing these receptors as well as adaptor proteins is a critical step in this process. A full understanding of the mechanisms underlying these relationships with the ultimate aim of abrogating specific steps, should lead to more targeted strategies for treatment of hormone-dependent breast cancer.
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 Consensus Statement Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S1 - S2. [Full Text] [PDF]
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