ER ER ER ER - Endocrine Reviews

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