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 α (ERα) and β (ERβ), respectively. Binding of agonists to the ERs affects gene transcription. The main endogenous estrogen, 17β-estradiol (E2), binds to both ERα and ERβ with similar affinity. However, the ligand-binding pocket of ERα and ERβ are slightly different which has allowed the development of selective ER ligands. Importantly, while estrogens via ERα stimulate proliferation, signaling via ERβ 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 ERα and ERβ 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 ERβ selective agonists inhibit growth and induce apoptosis in human and murine lymphomas in vivo in xenograft experiments. This suggests that ERβ selective agonists in the future may be useful in the treatment of lymphomas.