Modulation of breast cancer growth by modulation of xbp1 activity

Abstract

Described herein is a previously unknown function of XBP1 in triple-negative breast cancer (TNBC). It is shown that XBP1 is preferentially spliced and activated in TNBC, and that deletion of XBP1 significantly blocks triple negative breast tumor growth. Strikingly, XBP1 is required for the self-renewal of breast tumor initiating cells (TICs). Genome-wide mapping of the XBP1 transcriptional regulatory network identified a fundamental role for XBP1 in regulating the response to hypoxia via the transcription factor hypoxia-inducible factor 1a (HIF1a). Importantly, activation of this pathway appears to carry prognostic implications, as expression of the XBP1-dependent signature is associated with shorter survival times in human TNBC.

1 . A method of treating triple negative breast cancer (TNBC) in a subject, the method comprising administering to the subject a direct or indirect inhibitor of XBP1 in an amount effective to inhibit growth of cancer cells in said subject, such that TNBC in the subject is treated. 
     
     
         2 . The method of  claim 1 , wherein the subject has an advanced stage of breast cancer. 
     
     
         3 . The method of  claim 1 , wherein the inhibitor of XBP1 is a direct inhibitor. 
     
     
         4 . The method of  claim 3 , wherein the inhibitor of XBP1 is selected from the group consisting of a nucleic acid molecule that is antisense to an XBP1-encoding nucleic acid molecule, an XBP1 shRNA, an XBP siRNA, a microRNA that targets XBP1, a dominant negative XBP1 molecule and a small molecule inhibitor of XBP1. 
     
     
         5 . The method of  claim 4 , wherein the inhibitor of XBP1 is an XBP1 shRNA or an XBP siRNA. 
     
     
         6 . The method of  claim 1 , wherein the inhibitor of XBP1 is an indirect inhibitor. 
     
     
         7 . The method of  claim 6 , wherein the inhibitor of XBP1 is an agent that inhibits IRE1 or an agent that inhibits an endonuclease that produces XBP1s. 
     
     
         8 . The method of  claim 1 , wherein the inhibitor of XBP1 is administered to breast tissue of said subject. 
     
     
         9 . The method of  claim 8 , wherein the inhibitor of XBP1 is administered directly to a tumor in said tissue. 
     
     
         10 . The method of  claim 1 , wherein the inhibitor of XBP1 is administered in combination with a second cancer therapeutic agent. 
     
     
         11 . The method of  claim 10 , wherein the inhibitor of XBP1 is administered in combination with a chemotherapeutic agent. 
     
     
         12 . The method of  claim 1 , wherein the treatment promotes longer relapse-free survival of the subject. 
     
     
         13 . A method for determining a prognosis status for a subject with triple negative breast cancer (TNBC), the method comprising:
 a) determining an XBP1 gene signature for the TNBC of the subject; and   b) correlating the XBP1 gene signature with a prognosis status for the subject, wherein higher expression of the XBP1 gene signature, relative to a control, correlates with shorter relapse-free survival of the subject and lower expression of the XBP1 gene signature, relative to a control, correlates with longer relapse-free survival of the subject.   
     
     
         14 . The method of  claim 13 , wherein higher expression of the XBP1 gene signature, relative to a control, correlates with shorter relapse-free survival of the subject. 
     
     
         15 . The method of  claim 14 , wherein the XBP1 gene signature comprises a plurality of genes set forth in Table 1. 
     
     
         16 . The method of  claim 15 , wherein at least 5% of the genes set forth in Table 1 are expressed at a higher level relative to control. 
     
     
         17 . The method of  claim 15 , wherein at least 20% of the genes set forth in Table 1 are expressed at a higher level relative to control. 
     
     
         18 . The method of  claim 13 , wherein the gene signature is determined for a population of cells isolated from a breast tissue tumor breast of said subject. 
     
     
         19 . The method of  claim 13 , wherein the gene signature is determined for a population of cancer cells isolated from said subject. 
     
     
         20 . The method of  claim 13 , wherein the subject is negative for one or more of estrogen receptor (ER), progesterone receptor (PR) or Her2/neu. 
     
     
         21 . The method of  claim 13 , wherein the subject is positive for BRCA1. 
     
     
         22 . The method of  claim 21 , wherein the subject is further subjected to histopathological analysis of tumors. 
     
     
         23 . A method of identifying a compound useful in inhibiting the growth of triple negative breast cancer (TNBC) cells, the method comprising:
 a) providing an indicator composition comprising XBP1 and HIF1α, or biologically active portions thereof;   b) contacting the indicator composition with each member of a library of test compounds;   c) selecting from the library of test compounds a compound of interest that decreases the interaction of XBP1 and HIF1α, or biologically active portions thereof, wherein the ability of a compound to inhibit growth of TNBC cells is indicated by a decrease in the interaction as compared to the amount of interaction in the absence of the compound.   
     
     
         24 . The method of  claim 20 , wherein the subject is positive for BRCA1.