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who received tamoxifen adjuvant therapy was associated with an inferior clinical<br />
outcome, which is indicative of tamoxifen resistance (12, 46).<br />
In addition to the “classical” mode of action of <strong>ER</strong> regulating the expression of genes that<br />
harbor <strong>ER</strong>E elements in their promoter region, <strong>ER</strong> can also regulate gene transcription at<br />
DNA sites responsive to other transcription factors (40). Via this so called “non-<br />
classical” mode , nuclear <strong>ER</strong> protein interacts with other transcription factors such as SP-<br />
1 and members of the fos/jun AP1 transcription complex, leading to regulation of gene<br />
expression at non-<strong>ER</strong>E regulatory DNA sequences (figure 1B) (40, 47, 48).<br />
Importantly, signaling from different growth factor receptor-dependent kinases<br />
phosphorylates various factors in the <strong>ER</strong> pathway, including <strong>ER</strong> itself; this potentiates<br />
<strong>ER</strong> genomic signaling activity on gene transcription. As an example, kinase-induced<br />
phosphorylation of nuclear <strong>ER</strong> on serine 305 (49-51) enhances cyclin D1 transcription in<br />
breast cancer. Similarly, activation of the growth factor dependent signaling of p42/44<br />
mitogen-activated protein kinase (MAPK) (<strong>ER</strong>K 1 /2) and phosphatidyl inositol 3-kinase<br />
(PI3K)/AKT leads to an increase in <strong>ER</strong> serine 118 and serine 167 phosporylation and <strong>ER</strong><br />
AF-1 activity (52-54). This phosphorylation of <strong>ER</strong> and its co-regulatory proteins by<br />
growth factor receptor-dependent kinases is an essential component of the ordinary<br />
regulation and function of genomic <strong>ER</strong> activity. However, in the presence of hyperactive<br />
growth factor receptor signaling, as often occurs in breast cancer (e.g. H<strong>ER</strong>2<br />
overexpression), an excessive phosphorylation of <strong>ER</strong> and its co-regulators may severely<br />
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