Since the intrinsic or acquired resistance to the selective estrogen receptor modulators is a major obstacle in the management of breast cancers, our studies of UCH-L1 as a regulator of ERα may explain, at least in part, why ERα content is low or lost in a fraction of breast cancers, and may provide a basis for new approaches to up-regulating or maintaining ERα level. This evidence concerns the gene ESR1 and breast cancer.