AIB1, a novel steroid receptor co-activator

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.

1 . 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.   
     
     
         2 . 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. 
     
     
         3 . The method of  claim 2 , wherein the aberrantly proliferating cell is a steroid hormone-responsive cancer cell. 
     
     
         4 . The method of  claim 3 , wherein the steroid hormone-responsive cancer cell is a breast cancer cell. 
     
     
         5 . The method of  claim 3 , wherein the cell is a steroid hormone-responsive cancer cell is an ovarian cancer cell. 
     
     
         6 . The method of  claim 1 , wherein the AIB1 gene expression is measured using an AIB1 gene-specific polynucleotide probe. 
     
     
         7 . The method of  claim 1 , wherein the AIB1 gene expression is measured using an antibody that specifically binds AIB1. 
     
     
         8 . 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. 
     
     
         9 . The method of  claim 8 , wherein the number of copies in the tissue is greater than 2. 
     
     
         10 . The method of  claim 9 , wherein the number of copies in the tissue is greater than 10. 
     
     
         11 . The method of  claim 10 , wherein the number of copies in the tissue is greater than 20. 
     
     
         12 . A method of reducing proliferation of a cancer cell in a mammal comprising administering to the mammal a compound which inhibits expression of AIB1. 
     
     
         13 . The method of  claim 12 , wherein the compound reduces transcription of DNA encoding AIB1 in the cell. 
     
     
         14 . The method of  claim 12 , wherein the compound reduces translation of an AIB1 mRNA into an AIB1 gene product in the cell. 
     
     
         15 . The method of  claim 14 , wherein the translation is reduced by contacting the AIB1 mRNA with an antisense DNA complementary to the AIB1 mRNA. 
     
     
         16 . 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. 
     
     
         17 . The method of  claim 16 , wherein the polypeptide comprises a PAS domain. 
     
     
         18 . The method of  claim 16 , wherein the polypeptide comprises a bHLH domain. 
     
     
         19 . The method of  claim 16 , wherein the polypeptide comprises an ER-interacting domain 
     
     
         20 . 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.   
     
     
         21 . The method of  claim 20 , wherein the AIB1 gene expression is measured using an AIB1 gene-specific polynucleotide probe. 
     
     
         22 . The method of  claim 20 , wherein the AIB1 gene expression is measured using an antibody that specifically binds AIB1. 
     
     
         23 . 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. 
     
     
         24 . The method of  claim 23  wherein the molecule is p300 or CBP.