ER ER ER ER - Endocrine Reviews

estrogen receptor (MNAR), can activate growth factor (GF) tyrosine kinase receptors
(TKRs), such as EGFR and HER2 and the insulin-like growth factor I receptor (IGFR),
and cellular kinases such as c-Src. Cytoplasmic signaling molecules such as metastasis
associated gene 1 (MTA1)s can increase this non-nuclear fraction of ER. The interaction
between membrane/cytoplasmic ER and TKRs turns on the TKR pathways and their
downstream kinases, e.g. p42/44 MAPK (MAPK) and AKT. Other potential MISS
activity involves the activation, either directly or indirectly, of G-protein (GP)-coupled
receptors (GPCRs), which can then trigger various signaling processes including the
activation of c-Src and metalloproteinases (MMPs) and subsequent cleavage and release
of heparin-binding EGF (HB-EGF). The HB-EGF can then stimulate and activate the
EGFR/2 signaling pathway. TKR-induced kinases phosphorylate (P) nuclear ER and its
co-activators (CoA) as well as other transcription factors (TF), thus potentiating genomic
ER activity, which results in enhanced gene expression including genes in the TKR
pathways. These gene products in turn further augment GF-TKR signaling, thus
completing the cooperative cycle between the two activities of ER and their crosstalk
with the growth factor receptor and cellular kinase pathways. In the presence of excessive
TKR signaling, such as in HER2-overexpressing tumors, the nongenomic rapid ER action
may become more prominent. The resulting activation of downstream kinases can lead to
endocrine resistance by modifying the activity of various transcription factors and/or
negating the inhibitory effects of tamoxifen on nuclear ER.
FIGURE 3. Kaplan–Meier curves for disease-free survival (DFS) in tamoxifen-
treated patients according to the HER family receptor and PgR status. Among
tamoxifen-treated patients with ER+/PR+ tumors, neither EGFR nor HER2 had a
39