Regulation of cell growth by MUC1

Abstract

The invention features a method of identifying a compound that inhibits (a) the physical interaction (binding) between MUC1 and tumor progressors (e.g., β-catenin, c-Src, EGF-R, p120 ctn , or PKCδ) and/or (b) phosphorylation of MUC1 by tumor progressors with kinase activity (e.g., c-Src, EGF-R, or PKCδ). The invention also includes a method of inhibiting an interaction between MUC1 and β-catenin and a method of inhibiting expression of MUC1 or a tumor progressor in a cell.

What is claimed is:  
     
         1 . A method of identifying a compound that inhibits binding of MUC1 to a tumor progressor, the method comprising: 
 (a) providing a MUC1 test agent;    (b) providing a tumor progressor test agent that binds to the MUC1 test agent;    (c) contacting the MUC1 test agent with the tumor progressor test agent in the presence of a test compound; and    (d) determining whether the test compound inhibits binding of the MUC1 test agent to the tumor progressor test agent.    
     
     
         2 . The method of  claim 1 , wherein the tumor progressor test agent is a c-Src test agent.  
     
     
         3 . The method of  claim 1 , wherein the tumor progressor test agent is a p120 ctn  test agent.  
     
     
         4 . The method of  claim 1 , wherein the tumor progressor test agent is an epidermal growth factor receptor (EGF-R) test agent.  
     
     
         5 . The method of  claim 1 , wherein the tumor progressor test agent is a β-catenin test agent.  
     
     
         6 . The method of  claim 1 , wherein the tumor progressor test agent is a protein kinase Cδ (PKCδ) test agent.  
     
     
         7 . The method of  claim 1 , wherein the contacting is carried out in a cell-free system.  
     
     
         8 . The method of  claim 1 , wherein the contacting occurs in a cell.  
     
     
         9 . A method of identifying a compound that enhances binding of MUC1 to glycogen synthase kinase 3β (GSK3β), the method comprising: 
 (a) providing a MUC1 test agent;  
 (b) providing a GSK3β test agent that binds to the MUC1 test agent;  
 (c) contacting the MUC1 test agent with the GSK3β test agent in the presence of a test compound; and  
 (d) determining whether the test compound enhances binding of the MUC1 test agent to the GSK3β test agent.  
 
     
     
         10 . An in vitro method of inhibiting expression of MUC1 or a tumor progressor in a cell that expresses MUC1, the method comprising: (a) identifying a cell as expressing MUC1; and (b) treating the cell in vitro with an antisense oligonucleotide that hybridizes to a MUC1 transcript or to a tumor progressor transcript, wherein the antisense oligonucleotide inhibits expression of MUC1 or the tumor progressor in the cell.  
     
     
         11 . The method of  claim 10 , wherein the tumor progressor is selected from the group consisting of β-catenin, c-Src, p120 ctn , EGF-R, and PKCδ.  
     
     
         12 . The method of  claim 10 , wherein the cell is a cancer cell.  
     
     
         13 . The method of  claim 12 , wherein the cancer cell is a breast cancer cell.  
     
     
         14 . The method of  claim 12 , wherein the cancer cell is selected from the group consisting of a lung cancer, colon cancer, pancreatic cancer, renal cancer, stomach cancer, liver cancer, bone cancer, hematological cancer, neural tissue cancer, melanoma, ovarian cancer, testicular cancer, prostate cancer, cervical cancer, vaginal cancer, or bladder cancer cell.  
     
     
         15 . The method of  claim 10 , wherein the treating step is accomplished by introduction into the cell of a nucleic acid comprising a transcriptional regulatory element (TRE) operably linked to a nucleic acid sequence, wherein the nucleic acid sequence is transcribed in the cell into the antisense oligonucleotide.  
     
     
         16 . The method of  claim 15 , wherein the TRE is a DF3 enhancer.  
     
     
         17 . An in vivo method of inhibiting binding of MUC1 to β-catenin in a cancer cell that expresses MUC1, the method comprising: 
 (a) identifying a subject as having a cancer that expresses MUC1; and  
 (b) administering to the subject a compound or, where the compound is a polypeptide, a nucleic acid comprising a nucleic acid sequence encoding the polypeptide, 
 wherein the compound inhibits (i) binding of a tumor progressor to the cytoplasmic domain of MUC1 or (ii) phosphorylation of the cytoplasmic domain of MUJCI by a tumor progressor.  
 
 
     
     
         18 . The method of  claim 17 , wherein the tumor progressor is selected from the group consisting of β-catenin, c-Src, EGF-R, and PKCδ.  
     
     
         19 . The method of  claim 17 , wherein the compound is a peptide fragment of (a) MUC1 or (b) the tumor progressor.  
     
     
         20 . The method of  claim 19 , wherein the compound is a peptide fragment of the cytoplasmic domain of MUC1.  
     
     
         21 . The method of  claim 20 , wherein the peptide fragment comprises an amino acid sequence consisting of SEQ ID NO:7.  
     
     
         22 . The method of  claim 21 , wherein the amino acid sequence of the peptide fragment is SEQ ID NO:7.  
     
     
         23 . The method of  claim 17 , wherein the subject is a human subject.  
     
     
         24 . The method of  claim 17 , wherein the cancer cell is a breast cancer cell.  
     
     
         25 . The method of  claim 17 , wherein the cancer cell is selected from the group consisting of a lung cancer, colon cancer, pancreatic cancer, renal cancer, stomach cancer, liver cancer, bone cancer, hematological cancer, neural tissue cancer, melanoma, ovarian cancer, testicular cancer, prostate cancer, cervical cancer, vaginal cancer, or bladder cancer cell.  
     
     
         26 . The method of  17 , wherein the compound is a polypeptide and the treating step is accomplished by introduction into the cell of a nucleic acid comprising a TRE operably linked to a nucleic acid sequence encoding the polypeptide.  
     
     
         27 . The method of  claim 26 , wherein the TRE is a DF3 enhancer.  
     
     
         28 . A method of identifying a compound that inhibits phosphorylation of MUC1 by a tumor progressor, the method comprising: 
 (a) providing a MUC1 test agent;    (b) providing a tumor progressor test agent that phosphorylates the MUC1 test agent;    (c) contacting the MUC1 test agent with the tumor progressor test agent in the presence of a test compound; and    (d) determining whether the test compound inhibits phosphorylation of the MUC1 test agent by the tumor progressor test agent.    
     
     
         29 . An in vivo method of inhibiting expression of MUC1 or a tumor progressor in a cancer cell that expresses MUC1, the method comprising: 
 (a) identifying a subject as having a cancer that expresses MUC1; and    (b) administering to the subject an antisense oligonucleotide or a nucleic acid comprising a TRE operably linked to a nucleic acid sequence that is transcribed into the antisense oligonucleotide, 
 wherein the antisense oligonucleotide (i) hybridizes to a MUC1 transcript or to a tumor progressor transcript and (ii) inhibits expression of MUC1 or the tumor progressor in the cell.  
   
     
     
         30 . The method of  claim 29 , wherein the subject is a human patient.  
     
     
         31 . The method of  claim 29 , wherein the cancer cell is a breast cancer cell.