Glypican-1 is overexpressed in human breast cancer and modulates the mitogenic effects of multiple heparin-binding growth factors in breast cancer cells.
Glypicans are a family of glycosylphosphatidylinositol-anchored cell surface heparan sulfate proteoglycans implicated in the control of cellular growth and differentiation. Here we show that glypican-1 is strongly expressed in human breast cancers, whereas expression of glypican-1 is low in normal breast tissues. In contrast, the expression of glypican-3 and -4 is only slightly increased in breast cancers by comparison with normal breast tissues, and glypican-2 and -5 are below the level of detection by Northern blotting in both normal and cancer samples. Treatment of MDA-MB-231 and MDA-MB-468 breast cancer cells with phosphoinositide-specific phospholipase-C abrogated the mitogenic response to two heparin-binding growth factors, heparin-binding epidermal growth factor-like growth factor and fibroblast growth factor 2. Stable transfection of these cells with a glypican-1 antisense construct markedly decreased glypican-1 protein levels and the mitogenic response to the same heparin-binding growth factors, as well as that to heregulin alpha, heregulin beta, and hepatocyte growth factor. Syndecan-1 was also expressed at high levels in both breast cancer tissues and breast cancer cells when compared with normal breast tissues. There was a good correlation between glypican-1 and syndecan-1 expression in the tumors. However, clones expressing the glypican-1 antisense construct did not exhibit decreased syndecan-1 levels, indicating that loss of responsiveness to heparin-binding growth factors in these clones was not due to altered syndecan-1 expression. Furthermore, 8 of 10 tumors with stage 2 or 3 disease exhibited high levels of glypican-1 by Northern blot analysis. In contrast, low levels of glypican-1 mRNA were evident in 1 of 10 tumors with stage 2 or 3 disease and in 9 of 10 tumors with stage 1 disease. Taken together, these data suggest that glypican-1 may play a pivotal role in the ability of breast cancer cells to exhibit a mitogenic response to multiple heparin-binding growth factors and may contribute to disease progression in this malignancy.
Matsuda
K
K
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Biological Chemistry, and Pharmacology, University of California, Irvine, California 92697, USA.
Maruyama
H
H
Guo
F
F
Kleeff
J
J
Itakura
J
J
Matsumoto
Y
Y
Lander
A D
AD
Korc
M
M
D000328:Adult; D000368:Aged; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016373:DNA, Antisense / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006133:Growth Substances / Q000494:pharmacology*; D019812:Heparan Sulfate Proteoglycans / Q000032:analysis / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics; D008875:Middle Aged; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D011509:Proteoglycans / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053668:Syndecan-1; D053667:Syndecans; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism / Q000494:pharmacology
D016373:DNA, Antisense; D006133:Growth Substances; D019812:Heparan Sulfate Proteoglycans; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D012333:RNA, Messenger; C508241:SDC1 protein, human; D053668:Syndecan-1; D053667:Syndecans; D010738:Type C Phospholipases; D043265:Phosphatidylinositol Diacylglycerol-Lyase