Cross-Talk between Estrogen Receptor and Growth Factor Pathways as a Molecular Target for Overcoming Endocrine Resistance

Fig. 1.

Estrogen receptor (ER) and growth factor (GF) pathway cross-talk in endocrine resistance: a working model. The ligand estrogen (E) induces genomic-nuclear (N) ER activity, which results in increased gene transcription, including important genes in the growth factor pathways. Estrogen deprivation (−E2), the antiestrogen tamoxifen (T), and the potent antiestrogen fulvestrant (F) antagonize this activity. However, both estrogen and tamoxifen can turn on nongenomic membrane (M) and/or cytoplasmic (C) ER, which, in turn, through multiple interactions with signaling intermediate molecules (SIM; see text), can activate tyrosine kinase receptors (TKR) and cellular kinase cascades. Subsequent phosphorylation (P) of the ER and its coactivators (CoA) and corepressors (CoR) by these kinases (e.g., ERK/MAPK and AKT) then potentiates the genomic-nuclear ER activity. Increased GF signaling (by overexpression of GFs or TKRs) augments both activities of the ER and can result in endocrine resistance to antiestrogens like tamoxifen. This cycle can possibly be broken either by inhibitors of the GF/TKR pathways [TKIs or antibody (Ab) -based], which restore sensitivity to tamoxifen, or by abolition of the ER pathway by ligand deprivation or by ER degradation using fulvestrant (ERE, promoters containing diverse ER-responsive elements.)