An isoform of the coactivator AIB1 that increases hormone and growth factor sensitivity is overexpressed in breast cancer

The AIB1 (amplified in breast cancer 1) protein is a coactivator that poten tiates the transcriptional activity of nuclear hormone receptors, and its g ene is amplified in a subset of human breast cancers. Here we report a spli ce variant of AIB1 mRNA that lacks the exon 3 sequence. We determined that the AIB-Delta3 mRNA encoded a 130-kDa protein that lacks the NH2-terminal b asic helix-loop-helix and a portion of the PAS (Per-Arnt-Sim homology) dime rization domain. The 130-kDa protein was detected in MCF-7 breast cancer ce lls at levels that were 5-10% of the full-length protein, whereas in nontra nsformed mammary epithelium lines, the AIB-Delta3 protein was present at si gnificantly lower levels compared with the full-length AIB1. Consistent wit h this finding, the abundance of AIB1-Delta3 mRNA was increased in human br east cancer specimens relative to that in normal breast tissue. To determin e whether there were phenotypic changes associated with the overexpression of the AIB-Delta3 isoform, we performed functional reporter gene assays. Th ese revealed that the ability of AIB1-Delta3 to promote transcription media ted by the estrogen or progesterone receptors was significantly greater tha n that of the full-length protein. Surprisingly, the AIB1-Delta3 isoform wa s also more effective than AIB1 in promoting transcription induced by epide rmal growth factor. Overexpression of AIB1-Delta3 may thus play an importan t role in sensitizing breast tumor cells to hormone or growth factor stimul ation.