The immunomodulatory protein B7-H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation.
B7-H4 protein is expressed on the surface of a variety of immune cells and functions as a negative regulator of T cell responses. We independently identified B7-H4 (DD-O110) through a genomic effort to discover genes upregulated in tumors and here we describe a new functional role for B7-H4 protein in cancer. We show that B7-H4 mRNA and protein are overexpressed in human serous ovarian cancers and breast cancers with relatively little or no expression in normal tissues. B7-H4 protein is extensively glycosylated and displayed on the surface of tumor cells and we provide the first demonstration of a direct role for B7-H4 in promoting malignant transformation of epithelial cells. Overexpression of B7-H4 in a human ovarian cancer cell line with little endogenous B7-H4 expression increased tumor formation in SCID mice. Whereas overexpression of B7-H4 protected epithelial cells from anoikis, siRNA-mediated knockdown of B7-H4 mRNA and protein expression in a breast cancer cell line increased caspase activity and apoptosis. The restricted normal tissue distribution of B7-H4, its overexpression in a majority of breast and ovarian cancers and functional activity in transformation validate this cell surface protein as a new target for therapeutic intervention. A therapeutic antibody strategy aimed at B7-H4 could offer an exciting opportunity to inhibit the growth and progression of human ovarian and breast cancers.
Salceda
Susana
S
diaDexus, Inc., 343 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
Tang
Tenny
T
Kmet
Muriel
M
Munteanu
Andrei
A
Ghosh
Malavika
M
Macina
Roberto
R
Liu
Wenhui
W
Pilkington
Glenn
G
Papkoff
Jackie
J
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D018122:B7-1 Antigen / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D018076:DNA, Complementary / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006031:Glycosylation; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D018122:B7-1 Antigen; D018076:DNA, Complementary; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human