The anti-
estrogen,
tamoxifen is the most commonly used treatment for patients with
estrogen receptor (ER)-alpha-positive
breast cancer. Recent data suggest that levels of ER coregulatory
proteins as well as extra- and intracellular 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 has 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 are likely to be important determinants of
tamoxifen resistance, and that raising the possibility that
tamoxifen resistance might be prevented or reversed by PAK1 inhibition.