Estrogen receptor α and β in the normal immune system and in lymphoid malignancies

Estrogens regulate various normal and pathophysiological processes including cancers. Cellular signaling by estrogens is mediated by estrogen receptor alpha (ER alpha) and beta (ER beta), respectively. Binding of agonists to the ERs affects gene transcription. The main endogenous estrogen, 17 beta-estradiol (E-2), binds to both ER alpha and ER beta with similar affinity. However, the ligand-binding pocket of ER alpha and ER beta are slightly different which has allowed the development of selective ER ligands. Importantly, while estrogens via ER alpha stimulate proliferation, signaling via ER beta inhibits proliferation and promotes apoptosis. In both normal and cancer cells the ERs are co-expressed with ER splice variants which may modify the transcriptional activity of the wild-type receptors. Estrogens have prominent effects on immune functions and both ER alpha and ER beta are expressed in immune cells and lymphoid malignancies. With regard to lymphoid malignancies, most show estrogen influence as several epidemiological studies of lymphoid cancers demonstrate gender differences in incidence and prognosis with males being more affected. In line with these findings, recent results generated by us have shown that ER beta selective agonists inhibit growth and induce apoptosis in human and murine lymphomas in vivo in xenograft experiments. This suggests that ER beta selective agonists in the future may be useful in the treatment of lymphomas. (C) 2013 Elsevier Ireland Ltd. All rights reserved.