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

Exp Cell Res. 2005 May 15;306(1):128-41. 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.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • B7-1 Antigen / genetics*
  • B7-1 Antigen / metabolism
  • Blotting, Western
  • 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 Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • RNA, Small Interfering / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transfection
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • Xenograft Model Antitumor Assays / methods


  • B7-1 Antigen
  • DNA, Complementary
  • Membrane Glycoproteins
  • RNA, Small Interfering
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • VTCN1 protein, human