ER ER ER ER - Endocrine Reviews

independent or tamoxifen-mediated activation of the receptor (53, 54, 85).
Phosphorylation of ER co-regulators is probably no less important than phosphorylation
of ER itself in communicating these signal transduction effects on the ER pathway.
Phosphorylation of co-activators, similarly to that of the receptor, enhances the activity of
the co-activators themselves on the genomic ER even in the absence of its ligand or in the
presence of antiestrogens (42, 86). This phosphorylation potentiates the ability of
estrogen and SERMs to interact with ER and to recruit other transcriptional co-regulators
to its transcriptional complex (87); furthermore, it can directly activate their intrinsic
enzymatic activities (88). Phosphorylation of co-repressors, on the other hand, can result
in their export from the nucleus, thereby preventing their access to and inhibition of ER
transcriptional complexes in the nucleus (89).
The ER co-activator AIB1 has been shown to be phosphorylated and activated by
multiple kinases including MAPKs and other cellular kinases (86, 87, 90). Two
independent recent retrospective studies demonstrate that tumors with high levels of both
AIB1 and HER receptors (HER2 or HER3) are less responsive to tamoxifen therapy
probably because of increased estrogen agonistic activity of tamoxifen-bound ER (12,
46). Such findings support the hypothesis that increased signaling from the HER family
activates downstream kinases, which in turn activates ER and AIB1 increasing
transcriptional activity including in the presence of tamoxifen.
Finally, membrane functions of ER appear to depend not only on ER, but also on the
levels of growth factor receptors and their ligands (14, 17). This mode of ER signaling
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