Estrogen signaling has also been proposed to play a role in the homeostatic proliferative response of cholangiocytes in PBC. Accordingly, studies on polymorphisms in estrogen receptor genes revealed associations with the disease, at least in some populations [120] . At the tissue level, cholangiocytes from PBC patients in the earliest disease stages (but not cholangiocytes from normal controls) express estrogen receptors [121] . Agents able to modulate estrogen-receptor-mediated responses (such as tamoxifen) have therefore been proposed as novel, BEC homeostasis targeting therapies, and case reports support this hypothesis [122, 123] , but as yet, this potentially interesting therapeutic approach has not undergone formal assessment in clinical trials.