Figure 2. . Integration of genomic and nongenomic ER action and its crosstalk with growth factor receptor pathways in breast cancer: a working model.

In ER-positive breast tumors, genomic ER activity meditated by nuclear-initiated steroid signaling always predominates (see Figure 1), although some nongenomic signaling on acting ER that resides at the membrane and/or cytoplasm also occurs. This situation is usually upon acquisition of tamoxifen resistance or adaptation to hormone deprivation. Therefore, several tyrosine kinase receptors such as HER2 and EGFR as well as IGFR signaling become activated. Tyrosine kinase receptor-induced kinases phosphorylate nuclear ER and its CoA, thus promoting genomic ER activity and enhancing gene expression. As a result, genomic and nongenomic activities of ER and their crosstalk with growth factor tyrosine kinase pathways cooperative in promoting gene transcription, thus leading to endocrine resistance. Targeting the growth factor receptor pathway at different nodal points using antibodies (trastuzumab) and tyrosine kinase inhibitors (gefitinib, erlotinib and lapatinib) or other signal transduction inhibitors (e.g., mTOR inhibitors and MEK inhibitors) can eliminate the molecular crosstalk and overcome endocrine resistance.

CoA: Coactivator; ER: Estrogen receptor; ERE: Estrogen response element.

Adapted with permission from [10].