Role of a Novel Splice Variant of the Steroid Receptor Coactivator AIB1 in Breast Cancer

摘要

In this proposal we have investigated the hypothesis that overexpression of a novel truncated version of AIBl (Delta3AIBl) that we have found to be overexpressed in breast cancer is important for tumor development by impacting upon nuclear hormone receptor function. We have examined the hypothesis that the novel AIBl variant has an altered function that changes its interaction with nuclear receptors such as the estrogen or progesterone receptor. We propose that changes in the level of expression of the novel AIBl variant will support tumor progression and may well have prognostic significance for breast cancer. We have now determined that Delta3AIBl is overexpressed relative to the full-length protein in breast cancer tumor samples and cell lines. We have also determined that Delta3AIBl is a significantly more active coactivator that full-length AIBl on the estrogen and progesterone receptor (J. Biol. Chem. 276, 39736-39741, 2001). Delta3AIBl also plays a role in tamoxifen resistance and its overexpression makes tamoxifen a much more potent estrogen (Oncogene 23, 403-409, 2004). In addition, a surprising finding is that overexpression of Delta3AIBl can also potentiate EGF signaling. This implies that Delta3AIB1 can also drive hormone and non-hormone mediated proliferation in breast cancer.