WAP four-disulfide core domain protein 2 (WFDC2)

WAP four-disulfide core domain protein 2 (WFDC2), also known as Human Epididymis Protein 4 (HE4), is a small, secretory glycoprotein containing two WAP domains, characterized by eight cysteines forming four disulfide bonds at its core. While initially identified in the epididymis, WFDC2 is expressed in a range of tissues including pulmonary and oral epithelial cells and is notably upregulated in ovarian and some other cancers. Clinically, its main value is as a serum biomarker for ovarian cancer, providing higher sensitivity and specificity than CA125 in certain contexts. Functionally, it has been postulated to act as a protease inhibitor, but this role appears limited or context-dependent. In tumor biology, WFDC2 can promote cancer cell invasion in ovarian and oral cancer, but appears to play a tumor-suppressive role in prostate cancer by binding EGFR and inhibiting EGFR/AKT signaling, thereby reducing metastasis. There are currently no approved therapies that target WFDC2 directly, and its physiological roles include contributions to embryonic development of the respiratory tract. Note: HE4/WFDC2’s strong and clinically validated role is as a biomarker for ovarian cancer, not as a direct drug target, though its involvement in tumorigenesis suggests potential interest as a drug target in the future.

Other names

Human epididymis protein 4HE4WAP5dJ461P17.6EDDM4Epididymal secretory protein E4Major epididymis-specific protein E4Putative protease inhibitor WAP5epididymal protein 4BENPWAP domain containing protein HE4-V4epididymis secretory sperm binding protein

Biomarker use—no established drugs target WFDC2 directly; mechanistic interest centers on its putative protease inhibitor activity, modulation of cancer cell invasion, and interaction with EGFR signaling in prostate cancer.