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 alpha (ER(alpha)). The AIB1 gene and a more active N-terminally deleted isoform (AIB1-Delta3) are overexpressed in breast cancer. To determine the role of AIB1-Delta3 in breast cancer pathogenesis, we generated transgenic mice with human cytomegalovirus immediate early gene 1 (hCMVIE1) promoter-driven over-expression of human AIB1/ACTR-Delta3 (CMVAIB1/ACTR-Delta3 mice). AIB1/ACTR-Delta3 transgene mRNA expression was confirmed in CMV-AIB1/ACTR-Delta3 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-Delta3 mice, but secondary and tertiary branching patterns were normal. There were no changes in the expression patterns of either ER(alpha) 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-Delta3 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.
Tilli
Maddalena T
MT
Department of Oncology, Lombardi Cancer Center, Georgetown University, Research Building, Room E307, 3970 Reservoir Road, Washington, D.C. 20057, USA.
Reiter
Ronald
R
Oh
Annabell S
AS
Henke
Ralf T
RT
McDonnell
Kevin
K
Gallicano
G Ian
GI
Furth
Priscilla A
PA
Riegel
Anna Tate
AT
D017398:Alternative Splicing; D000818:Animals; D000956:Antigens, Viral / Q000235:genetics; D015139:Blotting, Southern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000196:embryology; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000378:metabolism; D008321:Mammary Glands, Animal; D042361:Mammary Glands, Human / Q000378:metabolism; D015674:Mammary Neoplasms, Animal; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000737:chemistry; D008957:Models, Genetic; D056921:Nuclear Receptor Coactivator 3; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000737:chemistry; D014157:Transcription Factors / Q000096:biosynthesis / Q000737:chemistry*; D019076:Transgenes; D025521:Tumor Suppressor Proteins
D000956:Antigens, Viral; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D017874:Immediate-Early Proteins; D008894:Milk Proteins; D020033:Protein Isoforms; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C044582:immediate-early proteins, cytomegalovirus; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I; D004247:DNA; D056921:Nuclear Receptor Coactivator 3; D017526:Receptor, IGF Type 1