Breast Cancer Susceptibility Gene GT198 and Uses Thereof

Abstract

It has been discovered that the human GT198 gene (gene symbol PSMC3IP) at chromosome 17q21 acts as a tumor suppressor. The mutation of the GT198 gene causes the increased dominant negative splice variant activity and leads to the loss of wild type GT198 function, and in turn, induces breast and ovarian cancers. One embodiment provides compositions and methods for treating or alleviating one or more symptoms associated with cancer due to the GT198 gene mutations. Another embodiment provides methods and compositions for detecting cancer due to the mutation of the GT198 gene. Still another embodiment provides methods for identifying compounds, antibodies and natural product molecules that are useful for treating cancer due to the mutations of the GT198 gene. Preferably the disclosed compositions antagonize or interfere with the biological activity of splice variants of GT198.

1 . A method for detecting or assisting in the diagnosis of cancer comprising:
 determining the presence of one or more mutations, alterations or rearrangments of the GT198 gene in a biological sample obtained from a subject by contacting the sample with a probe specific for the one or more mutations or alterations or rearrangments of the GT198 gene mutations, alterations or rearrangments or GT198 gene product to form a detectable complex between the probe and the GT198 gene mutations, alterations or rearrangments or gene product, wherein the presence of the detectable complex in the biological sample is indicative of cancer.   
     
     
         2 . The method of  claim 1 , wherein detecting the presence of one or more mutations or alterations of the GT198 gene is done by performing direct DNA sequencing on the sample. 
     
     
         3 . The method of  claim 1 , wherein detecting the presence of one or more DNA copy number changes is done by performing quantitative polymerase chain reaction. 
     
     
         4 . The method of  claim 1 , wherein detecting the presence of one or more DNA alterations or rearrangements is done by performing gel electrophoresis- and polymerase chain reaction-based analyses. 
     
     
         5 . The method of  claim 1 , wherein detecting the presence of GT198 and its variant protein expression is done by performing immunohistochemistry. 
     
     
         6 . The method of  claim 1 , wherein the biological sample is selected from the group consisting of blood, tissue, and cells. 
     
     
         7 . The method of  claim 1 , wherein the cancer is ovarian cancer. 
     
     
         8 . The method of  claim 1 , wherein the cancer is breast cancer. 
     
     
         9 . The method of  claim 1  wherein the mutation is a substitution in exon 4 of GT198. 
     
     
         10 . The method of  claim 9  wherein the mutation is C to T. 
     
     
         11 . The method of  claim 10  where the mutation is at nucleotide 85 of exon 4. 
     
     
         12 . The method of  claim 1  wherein the mutation causes increased expression of GT198 variant mRNA but decreased expression of the wild type GT198 mRNA. 
     
     
         13 . A method for diagnosing or assisting in the diagnosis of cancer comprising determining cytoplasmic expression levels of GT198 in a sample obtained from a subject by contacting the sample with a probe specific for GT198 to form a detectable complex between the probe and the GT198 gene product, wherein elevated cytoplasmic expression levels of GT198 relative to a control is indicative of cancer. 
     
     
         14 . A method for treating cancer comprising:
 administering to a subject an effective amount of an agent that inhibits biological activity or bioavailability of GT198 protein or its dominant negative variant proteins containing amino acid 126-217, or GT198 variant mRNA.   
     
     
         15 . The method of  claim 14  wherein the dominant negative variant protein is GT198a. 
     
     
         16 . The method of  claim 14 , wherein the agent comprises an antibody or antigen binding fragment thereof that specifically binds to GT198 or its dominant negative variant proteins under physiological conditions. 
     
     
         17 . The method of  claim 16 , wherein the antibody selected from the group consisting of monoclonal, polyclonal, single strand, humanized, and chimeric. 
     
     
         18 . The method of  claim 14  wherein the agent is selected from the group consisting of siRNA, microRNA, aptamer, and peptide nucleic acid. 
     
     
         19 . A method for treating cancer in subject comprising
 administering to the subject an effective amount of a GT198 antagonist or a GT198 variant antagonist to reduce the biological activity or bioavailability of GT198 or a variant there.   
     
     
         20 . A kit comprising
 a container comprising a nucleic acid probe comprising at least 10 nucleotides that hybridizes under stringent conditions to a nucleic acid encoding a GT198 variant protein and does not hybridize under stringent conditions to a nucleic acid encoding wild-type GT198.