Membrane initiated estrogen signaling in breast cancer.
Recent research has focused on effects of the estrogen receptor acting at the level of the cell membrane in breast cancer. In this review we describe 17beta-estradiol (E2)-initiated membrane signaling pathways involving the activation of several kinases that contribute to the regulation of cell proliferation and prevention of apoptosis. Although classical concepts had assigned priority to the nuclear actions of estrogen receptor, recent studies document the additional importance of estrogen receptor residing in or near the plasma membrane. A small fraction of estrogen receptor is associated with the cell membrane and mediates the rapid effects of E2. Unlike classical growth factor receptors, such as insulin-like growth factor 1 receptor (IGF1R) and epidermal growth factor receptor (EGFR), estrogen receptor has no transmembrane and kinase domains and is known to initiate E2 rapid signals by forming a protein complex with many signaling molecules. The formation of the protein complex is a critical step, leading to the activation of the MAPK1/3 (also known as MAP kinase) and AKT1 (also known as Akt) pathways. 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.
Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22903, USA. rs5wf@virginia.edu
Robert X-D
RX
Song
Richard J
RJ
Santen
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D066246:ErbB Receptors / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases
D047628:Estrogen Receptor alpha; D008565:Membrane Proteins; D017451:Receptors, Somatomedin; D004958:Estradiol; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3