Glypican-1 in human breast cancer

Abstract

Glycosylphosphatidylinositol-(GPI-) anchored HSPG glypican-1 is strongly expressed in human breast and pancreatic cancer—both by the cancer cells and in the case of pancreatic cancer the adjacent fibroblasts—whereas expression of glypican-1 is low in the normal pancreas and in chronic pancreatitis. Treatment of two pancreatic cancer cell lines, which express glypican-1, with the enzyme phosphoinositide-specific phospholipase-C (PI-PLC) abrogated their mitogenic responses to two heparin-binding growth factors: fibroblast growth factor-2 (FGF2) and heparin-binding EGF-like growth factor (HB-EGF). Treatment of MDA-MB-231 and MDA-MB-468 breast cancer cells with PI-PLC abrogates the mitogenic response to two heparin-binding growth factors, heparin-binding epidermal growth factor-like growth factor (HB-EGF) and fibroblast growth factor-2 (FGF-2). Syndecan-1 is also expressed at high levels in breast cancer tissues as well as breast cancer cells by comparison with breast normal tissues. Temporary or permanent transfection of a glypican-1 antisense construct attenuated glypican-1 protein levels and the mitogenic response to FGF2 and HB-EGF. Glypican can be used to detect the carcinoma in vitro and therapeutics that either bind to (e.g., antibodies or drugs), remove (e.g., enzymes) or prevent the expression (e.g., antisense constructs) of surface of the extracellular domain of glypican-1 are effective in retarding the growth of glypican-responsive carcinomas.

1 - 21 . (canceled)  
     
     
         22 . A therapeutic composition for treatment of a human cancer that is characterized by overexpression of glypican-1 as compared to a corresponding healthy tissue comprising a molecule that alters glypican-1 on a surface of a cancer cell by at least one of binding to the glypican-1, cleaving an extracellular region of glypican-1, and suppressing expression of the glypican-1.  
     
     
         23 . The therapeutic agent of  claim 22 , wherein the molecule comprises an antibody the binds to the extracellular region of glypican-1.  
     
     
         24 . The therapeutic agent of  claim 22 , wherein the molecule suppresses expression of the extracellular region of glypican-1.  
     
     
         25 . The therapeutic agent of  claim 22 , wherein the molecule comprises an enzyme that digests a portion of the extracellular region of glypican-1.  
     
     
         26 . The therapeutic agent of  claim 22 , wherein the molecule comprises a nucleic acid molecule that suppresses expression of the extracellular region of glypican-1.  
     
     
         27 . The therapeutic agent of  claim 26  comprising an nucleic acid molecule that is antisense to a nucleic acid sequence of glypican-1.  
     
     
         28 . A method for treating a human cancer that is characterized by overexpression of glypican-1 as compared to a corresponding healthy tissue comprising administering an amount of a molecule that affects glypican-1 by one of binding to an extracellular region of glypican-1, cleaving an extracellular region of glypican-1, and suppressing expression of glypican-1.  
     
     
         29 . The method of  claim 28 , wherein the molecule comprises an antibody the binds to the extracellular region of glypican-1.  
     
     
         30 . The method of  claim 28 , wherein the molecule comprises an enzyme that digests a portion of the extracellular region of glypican-1.  
     
     
         31 . The method of  claim 28 , wherein the molecule comprises a nucleic acid molecule that suppresses expression of glypican-1.  
     
     
         32 . The method of  claim 31 , wherein the nucleic acid molecule is antisense to a nucleic acid sequence of glypican-1.  
     
     
         33 . The method of  claim 31 , wherein the nucleic acid molecule suppresses expression of the extracellular region of glypican-1.  
     
     
         34 . The method of  claim 31  further comprising a step of transfecting human breast cancer cells with a nucleic acid molecule that alters expression of glypican-1.