The role of coactivators in oestrogen action

Excerpt

Several classes of coregulatory molecules are felt to play important roles in cell-type specific responses to oestrogens. These ER coactivators include members of the SWI2/SNF2 chromatin remodelling complexes, histone acetyltransferases such as p300/CBP, and p160 factors of the SRC-1 family. We sought to understand more fully how growth factors modulate oestrogen receptor activity in both normal oestrogen physiology and the pathogenesis of breast cancer. Growth factors are known to stimulate the ligand-independent activity of ER through the activation of MAPK and the direct phosphorylation of ER. We have now found that the transcriptional stimulatory activity of the p160 factor AIB1, a gene amplified preferentially in ER-positive breast cancers, is enhanced by MAPK. We show that AIB1 is a phosphoprotein in vivo and can be phosphorylated in vitro by MAPK. Finally we observe that MAPK activation of AIB1 stimulates the recruitment of p300 and associated histone acetyltransferase activity. These results suggest that the ability of growth factors to modulate oestrogen action may be mediated through MAPK activation of the nuclear receptor coactivator AIB1. In addition they suggest a potential point of cross-talk between growth-factor signalling pathways and oestrogen signalling in ER-positive breast cancers. …