Overexpression of an N-Terminally Truncated Isoform of the Nuclear Receptor Coactivator Amplified in Breast Cancer 1 Leads to Altered Proliferation of Mammary Epithelial Cells in Transgenic Mice

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2005-03, Vol.19 (3), p.644-656
• Main Authors: Tilli, Maddalena T, Reiter, Ronald, Oh, Annabell S, Henke, Ralf T, McDonnell, Kevin, Gallicano, G. Ian, Furth, Priscilla A, Riegel, Anna Tate
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Animals; Antigens, Viral - genetics; Blotting, Southern; Blotting, Western; Breast Neoplasms - embryology; Cell Proliferation; Cyclin D1 - metabolism; DNA - metabolism; DNA-Binding Proteins - chemistry; Enzyme-Linked Immunosorbent Assay; Epithelial Cells - metabolism; Estrogen Receptor alpha - metabolism; Gene Expression Regulation; Genotype; Human cytomegalovirus; Humans; Immediate-Early Proteins - genetics; Immunoblotting; Immunohistochemistry; In Situ Hybridization; Insulin-Like Growth Factor I - biosynthesis; Insulin-Like Growth Factor I - metabolism; Mammary Glands, Animal; Mammary Glands, Human - metabolism; Mammary Neoplasms, Animal; Mice; Mice, Transgenic; Milk Proteins - chemistry; Models, Genetic; Nuclear Receptor Coactivator 3; Promoter Regions, Genetic; Protein Isoforms; Receptor, IGF Type 1 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; STAT5 Transcription Factor; Trans-Activators - chemistry; Transcription Factors - biosynthesis; Transcription Factors - chemistry; Transgenes; Tumor Suppressor Proteins
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2004-0106

Amplified in breast cancer 1 (AIB1, also known as ACTR, SRC-3, RAC-3, TRAM-1, p/CIP) is a member of the p160 nuclear receptor coactivator family involved in transcriptional regulation of genes activated through steroid receptors, such as estrogen receptor α (ERα). The AIB1 gene and a more active N-terminally deleted isoform (AIB1-Δ3) are overexpressed in breast cancer. To determine the role of AIB1-Δ3 in breast cancer pathogenesis, we generated transgenic mice with human cytomegalovirus immediate early gene 1 (hCMVIE1) promoter-driven over-expression of human AIB1/ACTR-Δ3 (CMVAIB1/ACTR-Δ3 mice). AIB1/ACTR-Δ3 transgene mRNA expression was confirmed in CMV-AIB1/ACTR-Δ3 mammary glands by in situ hybridization. These mice demonstrated significantly increased mammary epithelial cell proliferation (P < 0.003), cyclin D1 expression (P = 0.002), IGF-I receptor protein expression (P = 0.026), mammary gland mass (P < 0.05), and altered expression of CCAAT/enhancer binding protein isoforms (P = 0.029). At 13 months of age, mammary ductal ectasia was found in CMV-AIB1/ACTR-Δ3 mice, but secondary and tertiary branching patterns were normal. There were no changes in the expression patterns of either ERα or Stat5a, a downstream mediator of prolactin signaling. Serum IGF-I levels were not altered in the transgenic mice. These data indicate that overexpression of the AIB1/ACTR-Δ3 isoform resulted in altered mammary epithelial cell growth. The observed changes in cell proliferation and gene expression are consistent with alterations in growth factor signaling that are thought to contribute to either initiation or progression of breast cancer. These results are consistent with the hypothesis that the N-terminally deleted isoform of AIB1 can play a role in breast cancer development and/or progression.