Sliding p21-activated kinase 1 to nucleus impacts tamoxifen sensitivity - 09/07/08
Abstract |
The anti-estrogen, tamoxifen is the most commonly used treatment for patients with estrogen receptor alpha (ER)-positive breast cancer. Recent data suggest that levels of ER coregulatory proteins as well as extra- and intra-cellular signaling in response to growth factor stimulation of breast cancer cells play an important role in acquiring resistance to anti-estrogen action. p21-activated kinase 1 (PAK1), a major target of the small GTPases, growth factors and lipid signaling, regulates cell motility, hormone action, invasiveness, and survival, all of which are required for both tumor development and normal mammary gland development. Over the years, the PAK1 have been regarded as cytosolic serine–threonine kinase with regulatory function in cytoskeleton reorganization and motility. However, emerging data now provide evidence of PAK1 function in the nucleus of breast cancer cells. Elevated PAK1 expression in premenopausal breast cancer patients correlates well with the lack of tamoxifen response despite the presence of ER-alpha expression, and such relationship was even distinctly stronger in breast tumors with nuclear PAK1. These typical effects of PAK1 are mechanistically linked with the ability of PAK1 to phosphorylate ER-alpha on serine 305, accompanied by secondary activation of serine 118 and, such structural modifications may participate in the development of tamoxifen resistance. These findings suggest that the levels, subcellular localization, and activation status of PAK1 is likely to be an important determinant of tamoxifen resistance, and that raising the possibility that tamoxifen resistance might be prevented or reversed by PAK1 inhibition.
El texto completo de este artículo está disponible en PDF.Keywords : PAK1, Estrogen receptor, Tamoxifen
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