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II. The H<strong>ER</strong> tyrosine kinase receptor family and its role in the development<br />
of endocrine resistance -- Studies in preclinical models<br />
As briefly discussed above, while the <strong>ER</strong>, via its membrane and nuclear activities,<br />
upregulates growth factor signaling, the molecular crosstalk between these two pathways<br />
is continuous and bi-directional. Signaling from multiple signal transduction pathways<br />
can modulate both the genomic and non-genomic activities of the <strong>ER</strong> pathway and their<br />
ligand dependency. In the section that follows, we will discuss in detail how this cross-<br />
talk, especially between the <strong>ER</strong> and H<strong>ER</strong> family, contributes to endocrine resistance.<br />
A. H<strong>ER</strong>/<strong>ER</strong> crosstalk as a mechanism for endocrine therapy resistance: Molecular<br />
determinants.<br />
Growth factor signaling plays an important role in the development of both de novo and<br />
acquired resistance of breast cancer cells to endocrine manipulation.<br />
It has been demonstrated that <strong>ER</strong> can be phosphorylated and activated by several<br />
intracellular kinases (42, 83). In particular, <strong>ER</strong> is phosphorylated at key residues<br />
(including serine 106/107, 118, 167, 305 and threonine 311) residing mainly in the AF-1<br />
domain, following p42/44 MAPK, PI3K/AKT, p90rsk, p21-activated kinase 1 Pak1,<br />
protein kinase A (PKA), or p38 MAPK pathway activation by various cytokines and<br />
growth factors including ligands of EGFR or IGF1R (42, 49-52, 54, 84). <strong>ER</strong><br />
phosphorylation has been shown to change <strong>ER</strong> pharmacology and can result in ligand-<br />
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