New Insights on Estrogen Receptor Actions in Hormone-responsive Breast Cancer Cells by Interaction Proteomics

Estrogens are tumor promoters for the mammary gland, due to their ability to control multiple functions of target cells and to stimulate their proliferation. The mechanisms that underlie control of cell proliferation by estrogens are still not fully defined, despite the important causal relationships between this hormonal action, mammary gland carcinogenesis and breast cancer (BC) progression. Estrogens exert their actions in target tissues via two intracellular receptors, ERalpha (ERα) and ERbeta (ERβ), that show specific, and often antagonist, roles and can be found co-expressed in BC where, however, ERα appears to prevail in mediating estrogen actions. ERs are ligand-dependent transcription factors of the nuclear receptor superfamily of intracellular regulators and their activity is tightly controlled by hormonal and non-hormonal ligands. This notion led to the design of synthetic ER antagonist ligands, including steroidal and non-steroidal antiestrogens, that are effective to inhibit BC cell proliferation and, for this reason, widely used for treatment of hormone-responsive tumors. These drugs, however, exhibit side effects that limit their efficacy and use. Studies based on application of genomics and proteomics are revealing new insights on estrogen signaling in BC cells, with the discovery of novel ER partner proteins promising as potential novel drug targets. We review here the new insights on ER signaling derived by systematic application of interaction proteomics to map and characterize the intracellular network of proteins binding to agonist- and/or antagonist-activated ERα in a hormone-responsive human BC cell model