The immunomodulatory protein B7-H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation

• Published in: Experimental cell research 2005-05, Vol.306 (1), p.128-141
• Main Authors: Salceda, Susana, Tang, Tenny, Kmet, Muriel, Munteanu, Andrei, Ghosh, Malavika, Macina, Roberto, Liu, Wenhui, Pilkington, Glenn, Papkoff, Jackie
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Apoptosis - physiology; B7-1 Antigen - genetics; B7-1 Antigen - metabolism; B7-H4; B7x; Blotting, Western; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Membrane - chemistry; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; DNA, Complementary - genetics; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Gene Expression Regulation, Neoplastic - genetics; Glycosylation; Humans; Immunohistochemistry; Membrane Glycoproteins - analysis; Mice; Mice, SCID; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - genetics; Transfection; V-Set Domain-Containing T-Cell Activation Inhibitor 1; Xenograft Model Antitumor Assays - methods
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2005.01.018

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.