Materials and methods for diagnosing and predicting the course of prostate cancer

Abstract

Expression of Forkhead-box protein A1 (FOXA1), a transcription factor important for the normal development of the prostate gland is thought to be controlled by steroid hormones and GATA-3. Expression of FOXA1, GATA-3 and androgen receptor (AR) was retrospectively analyzed by immunohistochemistry (IHC) in a series of 80 primary tumors and 28 metastatic prostate cancers including 15 matched paired samples. High nuclear FOXA1 expression was seen in 19% of primary tumors and 89% of metastatic tumors (p<0.0001). FOXA1 expression correlated positively with tumor size, extra-prostatic extension, angiolymphatic invasion, AR and metastasis but did not correlate with age, tumor stage, Gleason score, presence of PIN or multifocality, seminal vesicle or perineural invasion and status of surgical excision margins. Expression of GATA-3 was not seen in either normal epithelium or tumor. High FOXA1 expression is associated with development of metastatic prostate cancer. Accordingly, FOXA1 expression can be used to classify patients at higher risk for metastases.

We claim: 
     
         1 . A method of diagnosing prostate cancer, comprising the steps of:
 contacting a sample from a patient with a first reagent, wherein the first reagent selectively interacts with at least a portion of an expression produce of the FOXA1 gene and wherein the interaction produces a detectable signal;   determining the level the transcription factor FOXA1 in the sample by measuring the detectable signal produced by the interaction between the first reagent and the gene product, and]   correlating the measured signal with the likelihood that the patient's prostate cancer will metastasize,
 wherein a low level FOXA1 expression indicates a lessened risk for metastasis; and 
 wherein a high level of FOXA1 expression indicates a greater risk for metastasis. 
   
     
     
         2 . The method according to  claim 1 , wherein the signal can be detected directly. 
     
     
         3 . The method according to  claim 1 , wherein the signal can be detected indirectly. 
     
     
         4 . The method according to  claim 1 , wherein the detectable signal is radioactive. 
     
     
         5 . The method according to  claim 1 , wherein the detectable signal is a change in color of at least a portion of the sample. 
     
     
         6 . The method according to  claim 1 , wherein the expression product of the FOXA1 gene is a segment of RNA. 
     
     
         7 . The method according to  claim 1 , wherein the expression product of the FOXA1 gene is a polypeptide. 
     
     
         8 . The method according to  claim 1 , further includes contacting a second reagent that interacts with the first reagent to produce a detectable signal. 
     
     
         9 . The method according to  claim 1 , wherein the first reagent that preferentially interacts with the expression product of FOXA1 is an antibody. 
     
     
         10 . The method according to  claim 9 , further including the step of:
 reacting the antibody bound to the FOXA1 expression produce with a second antibody that preferentially binds to the first antibody.   
     
     
         11 . The method according to  claim 9 , wherein the antibody is goat anti-human FOXA1 antibody. 
     
     
         12 . The method according to  claim 10 , wherein the second antibody is label so as to produce a detectable signal and reacts with goat anti-human FOXA1 antibody. 
     
     
         13 . The method according to  claim 1 , wherein the level of FOXA1 expression is determined by scoring the sample, in a method that includes the steps of:
 recording the intensity (I) of the signal produced by the sample after contacting the sample with the first reagent;   observing the percentage (P) of cells in the sample that produce a signal; and   determining the score of the sample by multiplying the recorded intensity (I) by the observed percentage (P) of cells.   
     
     
         14 . The method according to  claim 13 , wherein the intensity is graded according to the following scale: none (0); mild (+1); moderate (+2) and strong (+3). 
     
     
         15 . The method according to  claim 13 , wherein the percentage ranges from 0 to 100. 
     
     
         16 . The method according to  claim 13 , wherein the intensity is graded according to the following scale: none (0); mild (+1); moderate (+2) and strong (+3) and the percentage ranges from 0 to 100 and the signal ranges from 0 to 300. 
     
     
         17 . The method according to  claim 16 , wherein a sample with a level of FOXA1 expression product greater than about 275 is indicative of form of prostate cancer with a high likelihood of metastasizing. 
     
     
         18 . The method according to  claim 16 , wherein a sample with a level of FOXA1 expression product greater than about 280 is indicative of form of prostate cancer with a high likelihood of metastasizing. 
     
     
         19 . The method according to  claim 16 , wherein a sample with a level of FOXA1 expression product less than about 150 is indicative of form of prostate cancer with low likelihood of metastasizing. 
     
     
         20 . A method of screening for a compound to treat prostate cancer, comprising the steps of:
 providing a prostate cancer cell that expresses high level of the transcription factor FOXA1;   contacting said prostate cancer cell with at least one compound; and   measuring the viability of prostate cells after contacting said cells with the compound.   
     
     
         21 . The method according to  claim 21 , further including the step of identify compounds that selectively reduce the viability of prostate cancer cells that highly express FOXA1 without affecting non-cancerous prostate cancer cells. 
     
     
         22 . A method of treating prostate cancer; comprising the steps of:
 providing at least one compound or a pharmaceutically acceptable salt thereof that modulates the activity FOXA1 or a expression product of FOXA1;   treating a patent with the compound or a pharmaceutically acceptable salt thereof.   
     
     
         23 . The method according to  claim 22 , wherein the compound interferes with the expression of the FOXA1 gene. 
     
     
         24 . The method according to  claim 22 , wherein the compound interferes with a polynucleotide involved in the expression of the FOXA1 gene. 
     
     
         25 . The method according to  claim 22 , wherein the compound interferes with the transcription factor encoded by the FOXA1 gene