AIB1, a novel steroid receptor co-activator
AssigneeThe Govt. of the U.S.A. as represented by the Secretary of the Dept. of Health & Human Services
InventorsPaul Meltzer, Jeffrey Trent
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Abstract
The invention features a substantially pure DNA which includes a sequence encoding a novel steroid receptor co-activator which is overexpressed in breast cancer cells, diagnostic assays for steroid hormone-responsive cancers, and screening assays to identify compounds which inhibit an interaction of the co-activator with the steroid hormone.
Claims54
A substantially pure DNA comprising a sequence encoding an AIB1 polypeptide.
A substantially pure DNA comprising a polynucleotide which hybridizes at high stringency to a DNA having the sequence of SEQ. I.D. NO. 1, or the complement thereof.
A substantially pure DNA comprising a nucleotide sequence having at least 50% sequence identity to SEQ. I.D. NO. 1, the nucleotide sequence encoding a polypeptide having the biological activity of a AIB1 polypeptide.
A substantially pure DNA comprising (a) the sequence of SEQ. I.D. NO. 1 or (b) a degenerate variant thereof.
A substantially pure human AIB1 polypeptide.
A method of identifying a candidate compound which inhibits estrogen receptor (ER)-dependent transcription comprising contacting the compound with an AIB1 polypeptide and determining whether the compound binds to the polypeptide, wherein binding of the compound to the polypeptide indicates that the compound inhibits ER-dependent transcription.
A method of identifying a candidate compound which inhibits ER-dependent transcription comprising:
- contacting the compound with an AIB1 polypeptide and an ER polypeptide and determining the ability of the compound to interfere with the binding of the ER polypeptide with the AIB1 polypeptide.
A method of screening a candidate compound which inhibits an interaction of an AIB1 polypeptide with an ER polypeptide in a cell comprising
- (a) providing a GAL4 binding site linked to a reporter gene;
- (b) providing a GAL4 binding domain linked to either (i) an AIB1 polypeptide or (ii) an ER polypeptide;
- (c) providing a GAL4 transactivation domain II linked to the ER polypeptide if the GAL4 binding domain is linked to the AIB1 polypeptide or linked to the AIB1 polypeptide if the GAL4 binding domain is linked to the ER polypeptide;
- (d) contacting the cell with the compound;
- and
- (e) monitoring expression of the reporter gene, wherein a decrease in expression in the presence of the compound compared to that in the absence of the compound indicates that the compound inhibits an interaction of an AIB1 polypeptide with the ER polypeptide.
A method of detecting an aberrantly proliferating cell in a tissue sample comprising determining the level of AIB1 gene expression in the sample, wherein an increase in the level of expression compared to the level in normal control tissue indicates the presence of an aberrantly proliferating cell.
A method of detecting breast cancer in a tissue sample, comprising determining the number of cellular copies of an AIB1 gene in the tissue sample, wherein an increase in the number of copies compared to the number of copies in a normal control tissue indicates the presence of a breast carcinoma.
A method of reducing proliferation of a cancer cell in a mammal comprising administering to the mammal a compound which inhibits expression of AIB1.
A method of inhibiting ER-dependent transcription in a breast cell of an mammal, comprising administering an effective amount of an AIB1 polypeptide to the mammal.
A method of inhibiting ER-dependent transcription in a cancer cell of a mammal, comprising administering an effective amount of a peptide mimetic of an AIB1 polypeptide to the mammal.
A monoclonal antibody which binds specifically to AIB1.
A method of identifying a tamoxifen-sensitive patient, comprising
- (a) contacting a patient-derived tissue sample with tamoxifen;
- and
- (b) determining the level of AIB1 gene expression in the sample, wherein an increase in the level of expression compared to the level in normal control tissue indicates that the patient is tamoxifen-sensitive.
A transgenic animal wherein at least one copy of the AIB1 gene has been functionally deleted.
A transgenic mouse wherein at least one copy of the pCIP gene has been functionally deleted.
A transgenic animal genetically engineered to have more than the normal copy number of the AIB1 gene.
A transgenic animal having at least one AIB1 gene operatively linked to a non-native promoter.
A method of reducing proliferation of a cancer cell comprising administering to the mammal a compound which inhibits interaction of AIB1 with a molecule selected from the group consisting of steroid receptors and nuclear co-factors.
The method of claim 58 wherein the molecule is selected from the group consisting of:
- p300 and CBP.
Dependencies are inferred from the claim text.