Methods for treating breast cancer using NRIF3 related molecules

Abstract

Disclosed herein is the discovery that administration of the NRIF3 family of transcriptional coregulators (NRIF3 and related molecules) to breast cancer cells induce rapid and profound apoptosis (nearly 100% cell death within 24 h). A novel death domain (DD1) was mapped to a short 30 amino acid region common to all members of the NRIF3 family. Two other death domains (DD2 and DD3) were also found to have effective breast cancer killing activities. Mechanistic studies showed that DD1-induced apoptosis occurred through a novel caspase-2 mediated pathway that involved mitochondria membrane permeabilization but did not require other caspases. Interestingly, cytotoxicity of NRIF3 related molecules was cell-type specific, as they selectively killed breast cancer or related cells but not other examined cells of different origins, suggesting the presence in breast cancer cells of a specific death switch that can be selectively triggered by NRIF3 and related molecules. Also disclosed are strategies utilizing NRIF3 related molecules and/or targeting this death switch for the development of novel and more selective therapeutics against breast cancer.

1 . A method for treating a patient suffering from breast cancer comprising administering to a patient in need of such treatment an amount effective to treat breast cancer of an agent selected from NRIF3 related molecules and derivatives thereof.  
     
     
         2 . The method of  claim 1  wherein said agent causes apoptosis in said cancer cell.  
     
     
         3 . The method of  claim 2  wherein said agent is selected from full-length NRIF3, EnL, EnS, DD1, DD2, DD3 and mixture thereof.  
     
     
         4 . The method of  claim 1  wherein said derivatives are NRIF3 related molecules linked to cell permeation peptide sequences.  
     
     
         5 . The method of  claim 4  wherein said cell permeation peptide sequences are derived from the hydrophobic region of Kaposi fibroblast growth factor.  
     
     
         6 . The method of  claim 4  wherein said cell permeation peptide sequences are derived from the HIV tat protein.  
     
     
         7 . The method of  claim 1  wherein said derivative is an N-myristoylated polypeptide selected from NRIF3 related molecules.  
     
     
         8 . A pharmaceutical formulation for treating a mammal suffering from breast cancer comprising an agent selected from NRIF3 related molecules and derivatives thereof and a pharmaceutical acceptable carrier or diluent.  
     
     
         9 . An isolated polypeptide comprising an amino acid sequence consisting of DD1.  
     
     
         10 . An isolated polypeptide comprising an amino acid sequence consisting of DD2.  
     
     
         11 . An isolated polypeptide comprising an amino acid sequence consisting of DD3.  
     
     
         12 . An isolated nucleic acid comprising a nucleotide sequence consisting of DD1.  
     
     
         13 . An isolated nucleic acid comprising a nucleotide sequence consisting of DD2.  
     
     
         14 . An isolated nucleic acid comprising a nucleotide sequence consisting of DD3.  
     
     
         15 . The pharmaceutical formulation of  claim 8  wherein said NRIF3 related molecule is selected from full-length NRIF3. DD1, DD2, DD3, EnS, EnL and derivatives thereof.  
     
     
         16 . A method a method for killing a breast cancer cell comprising contacting said cell with an amount of an agent selected from NRIF3 related molecules and derivatives thereof effective to kill said cell.  
     
     
         17 . A method for treating a patient suffering from breast cancer comprising administering to a patient in need of such treatment an amount of a nucleic acid encoding NRIF3 related molecules effective to kill said cancer cell.  
     
     
         18 . The method of  claim 17  wherein said nucleic acid is administered in a viral vector.  
     
     
         19 . The method of  claim 17  wherein said nucleic acid comprises a naked DNA plasmid.