Breast cancer amplified sequence 2 (BCAS2) was initially identified as a gene that was overexpressed and amplified in some breast cancer cell lines. It was later found to be a component of the spliceosome. Here, we identified BCAS2 as an estrogen receptor (ER) alpha interacting protein by yeast two-hybrid screening. In addition to ERalpha, BCAS2 also interacted with ERbeta, TRbeta, PR, and PPARgamma in a ligand-independent way. Transient transfection assays revealed that overexpression of BCAS2 enhanced while inhibition of BCAS2 expression attenuated the estrogen receptor-mediated transcription. BCAS2 potentiated the activation function-2 (AF-2) activity of ERalpha but had no effect on the AF-1 activity. This study suggested that BCAS2 might play an important role in breast cancer development by increasing the estrogen receptor's function. (C) 2005 Elsevier Inc. All rights reserved.