Targeting pax2 for the treatment of breast cancer

Abstract

The present application provides methods of prevention and/or treatment of breast cancer in a subject by inhibiting expression of PAX2. In the cancer treatment methods disclosed, the method of inhibiting expression of PAX2 can be by administration of a nucleic acid encoding an siRNA for PAX2. A method of treating cancer in a subject by administering DEFB1 is also provided. Similarly, provided is a method of treating cancer in a subject by increasing expression of DEFB1 in the subject.

What is claimed is: 
     
         1 . A method of treating breast cancer in a subject, comprising administering to the subject an anti-PAX2 composition comprising an effective amount of an anti-PAX2 agent, wherein the anti-PAX2 agent is conjugated to a targeting moiety to target breast cancer tissue, and wherein the anti-PAX2 agent is an antagonist of PAX2. 
     
     
         2 . The method of  claim 1 , wherein the antagonist of PAX2 is a small molecule. 
     
     
         3 . The method of  claim 2 , wherein the small molecule is selected from the group consisting of. Losartan, PD123319, U0126, PD98059, 5-amino imidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), enalapril, valsartan, olmesartan, and telmisartan, or the small molecule is identified through combinatory or screening techniques. 
     
     
         4 . The method of  claim 1 , the targeting moiety is an antibody. 
     
     
         5 . The method of  claim 1 , wherein the targeting moiety is a receptor. 
     
     
         6 . The method of  claim 1 , wherein the targeting moiety is a receptor ligand. 
     
     
         7 . The method of  claim 1 , wherein said anti-PAX2 composition is administered intravenously. 
     
     
         8 . The method of  claim 1 , further comprising administering to the subject an adjuvant therapy. 
     
     
         9 . The method of  claim 8 , wherein the adjuvant therapy is selected from the group consisting of an anti-hormone therapy, an anti-ERRB2 therapy, an anti-HER2 therapy, an anti A1B1/SRC-3 therapy, tamoxifen, Herceptin, and trastuzumab. 
     
     
         10 . The method of  claim 1 , further comprising determining a PAX2-to-DEFB1 expression ratio in a breast cancer tissue from the subject, and determining the estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 (ER/PR/HER2) status of said breast cancer tissue from said subject. 
     
     
         11 . A method of preventing and/or delaying progression of breast cancer to invasive breast cancer in a subject comprising administering to the subject, an effective amount of an anti-PAX2 composition comprising one or more anti-PAX2 agents. 
     
     
         12 . The method of  claim 11 , wherein the one or more anti-PAX2 agents are selected from the group consisting of a polynucleotide encoding an siRNA for PAX2, a polynucleotide that blocks binding of PAX2 to a DEFB1 promoter, an anti-PAX2 antibody, an anti-PAX2 agent conjugated to an antibody, an anti-PAX2 vaccine, an antagonist of PAX2, an antagonist of angiotensin II, an antagonist of angiotensin II receptor, an antagonist of angiotensin-converting enzyme (ACE), an antagonist of mitogen-activated protein kinase (MEK), an antagonist of extracellular signal-regulated kinase (ERK) 1, ERK 2, an antagonist of signal transducer and activator of transcription 3 (STAT3), and a blocker of the renin-angiotensin system (RAS) signaling pathway. 
     
     
         13 . The method of  claim 11 , further comprising determining a PAX2-to-DEFB1 expression ratio in a breast cancer tissue from the subject, and determining the estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 (ER/PR/HER2) status of said breast cancer tissue from said subject. 
     
     
         14 . The method of  claim 11 , wherein the one or more anti-PAX2 agents are selected from the group consisting of a siRNA for PAX2 having the nucleic acid of SEQ ID NOs: 3-10, a polynucleotide that blocks binding of PAX2 to a DEFB1 promoter having the nucleic acid sequence of SEQ ID NOs: 18-30, Losartan, PD123319, U0126, PD98059, 5-amino imidale-4-carboxamide-1-β-4-ribo furano side (AICAR), enalapril, valsartan, olmesartan, and telmisartan, or a small molecule identified through combinatory or screening techniques. 
     
     
         15 . The method of  claim 11 , further comprising administering to the subject an adjuvant therapy. 
     
     
         16 . The method of  claim 15 , wherein the adjuvant therapy is selected from the group consisting of an anti-hormone therapy, an anti-ERRB2 therapy, an anti-HER2 therapy, an anti A1B1/SRC-3 therapy, tamoxifen, Herceptin, and trastuzumab. 
     
     
         17 . A method of preventing breast cancer in a subject comprising administering to the subject, an effective amount of an anti-PAX2 composition comprising one or more anti-PAX2 agents. 
     
     
         18 . The method of  claim 17 , wherein the one or more anti-PAX2 agents are selected from the group consisting of a polynucleotide encoding an siRNA for PAX2, a polynucleotide that blocks binding of PAX2 to a DEFB1 promoter, an anti-PAX2 antibody, an anti-PAX2 agent conjugated to an antibody, an anti-PAX2 vaccine, an antagonist of PAX2, an antagonist of PAX2, an antagonist of angiotensin II, an antagonist of angiotensin II receptor, an antagonist of angiotensin-converting enzyme (ACE), an antagonist of mitogen-activated protein kinase (MEK), an antagonist of extracellular signal-regulated kinase (ERK) 1, ERK 2, an antagonist of signal transducer and activator of transcription 3 (STAT3), and a blocker of the renin-angiotensin system (RAS) signaling pathway, or a small molecule identified through combinatory or screening techniques. 
     
     
         19 . The method of  claim 17 , further comprising determining a PAX2-to-DEFB1 expression ratio in a breast tissue from the subject and determining the estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 (ER/PR/HER2) status of said breast tissue from said subject. 
     
     
         20 . The method of  claim 19 , wherein the breast tissue is a normal breast tissue or a mammary intraepithelial (MIN) tissue.