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J. Biol. Chem., Vol. 276, Issue 43, 39736-39741, October 26, 2001
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From the Departments of Oncology and Pharmacology, Lombardi Cancer
Center, Georgetown University Medical Center, Washington, D. C. 20007
The AIB1 (amplified in breast cancer 1) protein
is a coactivator that potentiates the transcriptional activity of
nuclear hormone receptors, and its gene is amplified in a subset of
human breast cancers. Here we report a splice variant of
AIB1 mRNA that lacks the exon 3 sequence. We determined
that the AIB-
An Isoform of the Coactivator AIB1 That Increases Hormone
and Growth Factor Sensitivity Is Overexpressed in Breast Cancer*
3 mRNA encoded a 130-kDa protein that
lacks the NH2-terminal basic helix-loop-helix and a portion
of the PAS (Per-Arnt-Sim homology) dimerization domain. The 130-kDa
protein was detected in MCF-7 breast cancer cells at levels that were
5-10% of the full-length protein, whereas in non-transformed mammary
epithelium lines, the AIB-3 protein was present at significantly
lower levels compared with the full-length AIB1. Consistent with this
finding, the abundance of AIB1-3 mRNA was increased
in human breast cancer specimens relative to that in normal breast
tissue. To determine whether there were phenotypic changes associated
with the overexpression of the AIB-3 isoform, we performed
functional reporter gene assays. These revealed that the ability of
AIB1-3 to promote transcription mediated by the estrogen or
progesterone receptors was significantly greater than that of the
full-length protein. Surprisingly, the AIB1-3 isoform was also more
effective than AIB1 in promoting transcription induced by epidermal
growth factor. Overexpression of AIB1-3 may thus play an important
role in sensitizing breast tumor cells to hormone or growth factor stimulation.
*
This work was supported by grants from the United States
Department of Defense Breast Cancer Research Program (to
A. T. R.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 202-687-1479;
Fax: 202-687-4821; E-mail: ariege01@georgetown.edu.
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