Overexpression of the nuclear receptor coactivator AIB1, (SRC-3) during progression of pancreatic adenocarcinoma

Purpose: The nuclear receptor coactivator amplified in breast cancer 1 (AIB1) was found to be amplified and over-expressed in breast and some other epithelial tumors. We have reported that expression of AIB1 is rate limiting for growth factor, as well as hormone signaling. Here, we assess the involvement of AIB1 in the development of pancreatic adenocarcinoma. Experimental Design: We investigated expression levels of AIB1 protein and mRNA in pancreatic cancer cell lines and in a series of archival pancreatic adenocarcinoma (n = 78), pancreatic intraepithelial neoplasia (n = 93), pancreatitis (n = 28), and normal pancreas tissues (n = 52). We also determined AIB1 gene copy numbers by fluorescence in situ hybridization in a subset of cases. Results: In normal pancreas ducts, we rarely found detectable levels of AIB1 mRNA or protein (<6% of the samples). In pancreatitis and low-grade intraepithelial neoplasia, we found an increased frequency of AIB1 expression (>14 and >23%, respectively) relative to normal tissues (P < 0.01). Adenocarcinoma, as well as high-grade intraepithelial neoplasia, showed increased levels as well as the highest frequency of AIB1 expression with >65% of samples positive for mRNA and protein (P < 0.0001 relative to the other groups). An increased copy number of the AIB1 gene, observed in 37% of cancers, may account for a portion of the increase in expression. Conclusions: ATB1 overexpression is frequent. in pancreatic adenocarcinoma and its precursor lesions. On the basis of its rate-limiting role for the modulation of growth factor signals, we propose a major role of AIB1 in the multistage progression of pancreatic cancer.