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This version published online on November 18, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0106
A more recent version of this article appeared on March 1, 2005
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Submitted on March 12, 2004
Accepted on November 12, 2004

Overexpression of an N-Terminally Truncated Isoform of the Nuclear Receptor Coactivator AIB1/ACTR Leads to Altered Proliferation of Mammary Epithelial Cells in Transgenic Mice*

Maddalena T. Tilli*, Ronald Reiter, Annabell S. Oh, Ralf T. Henke, Kevin McDonnell, G. Ian Gallicano, Priscilla A. Furth, and Anna Tate Riegel

Departments of Oncology and Pharmacology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D. C. 20057

* To whom correspondence should be addressed. E-mail: paf3{at}georgetown.edu.

Amplified in Breast Cancer 1 (AIB1, a.k.a. 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-{Delta}3) are overexpressed in breast cancer. To determine the role of AIB1-{Delta}3 in breast cancer pathogenesis, we generated transgenic mice with human cytomegalovirus immediate early gene 1 (hCMVIE1) promoter-driven overexpression of human AIB1/ACTR-{Delta}3 (CMV-AIB1/ACTR-{Delta}3 mice). AIB1/ACTR-{Delta}3 transgene mRNA expression was confirmed in CMV-AIB1/ACTR-{Delta}3 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-1R protein expression (P = 0.026), mammary gland mass (P < 0.05), and altered expression of C/EBP{beta} isoforms (P = 0.029). At 13 months of age, mammary ductal ectasia was found in CMV-AIB1/ACTR-{Delta}3 mice but secondary and tertiary branching patterns were normal. There were no changes in the expression patterns of either ER{alpha} or Stat5a, a down-stream mediator of prolactin signaling. Serum IGF-I levels were not altered in the transgenic mice. These data indicate that overexpression of the AIB1/ACTR-{Delta}3 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.
Key words: AIB1 • AIB1-{Delta}3 • ACTR • coactivator • mouse model

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  PR
Coregulators:   AIB1



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