“Dwarf ” Estrogen Receptor in Breast Cancer and Resistance to

A major problem in breast cancer treatment and research today is why so many patients with estrogen receptor alpha (ER) –positive tumors have de novo resistance to tamoxifen and why even more acquire resistance at a later time. An interesting study by Shi et al in this issue of Journal ofClinicalOncology suggests that one mechanism (and there are probably many) involves a truncated variant of ER, which may predict and possibly mediate resistance.1 In previous studies, these investigators identified a novel 36-kDa variant of ER using a homology search against a portion of the ER66 ligand binding domain, and cloned it from human placental cDNA.2 Like ER66, this ER variant is expressed from the ESR1 gene, but it is transcribed from an alternative start site. Following transcription, it also undergoes alternative splicing at the 3 end, yield-ing a protein lacking the AF-1 and AF-2 trans-activation domains, as well as the last 138 amino acids of ER66, which are replaced with