An AIB1 isoform rewires glucocorticoid receptor signaling to promote TNBC progression

NCOA3, also known as the oncogene AIB1 (Amplified in Breast Cancer-1), is the third member of the p160 family of steroid receptor coactivators (SRC3). Using global alignment, we show that the genomic architecture of NCOA3/AIB1 is conserved across vertebrate and invertebrate species between exon 3 and the 3’UTR. In particular, the N-terminal domain is highly conserved with a cophenetic distance <2 between mouse and human. Interestingly, in both species the degree of exon skipping in this region between exons 3-10 is significantly higher than the rest of the gene. We have previously reported a naturally occurring mRNA isoform of human NCOA3/AIB1 that is generated by skipping of exon 4 (AIB1∆4) resulting in an N-terminally truncated protein missing the bHLH-PAS domain. AIB1∆4 is a potent transcriptional coactivator overexpressed in some human cancers and can increase their invasive potential. Here we report that in contrast to exon 4 skipping in human transcripts, murine mRNA showed recurrent skipping of exon 5 (AIB1∆5), especially in spleen and immune T and B cells, producing a protein with a similar mass to that of human AIB1∆4. Mass spectrometry confirmed that murine AIB1∆5 has an acetylated N-terminal start site 11 amino acids upstream of the start site of human AIB1∆4. We found that murine AIB1∆5 expression increases during malignant progression of tumors and is a potent coactivator of nuclear receptor transcriptional activity. Thus, our data indicate that the N-terminal region of NCOA3/AIB1 is a conserved “hot spot” of alternative splicing that modulates its activity.