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

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-t...

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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
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Summary: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.
ISSN:0888-8809
1944-9917
DOI:10.1210/me.2004-0106