The Human Epididymis Protein 4 (HE4), also known as the WAP four-disulfide core domain protein 2 (WFDC2), is a 25 kDa secreted glycoprotein and is expressed in the epididymis, uterus, and tracheal tissues. HE4 was detected in bronchiolar, endocervical, endometrial, vas deferens, and breast epithelium by immunohistochemical staining. Distal convoluted tubules in the kidneys were also immunoreactive.

The value of serum HE4 as a biomarker for ovarian and endometrial cancers has been well recognized. Overexpression of HE4 enhanced the malignant behavior of cancer cells including proliferation, invasion, and colony formation. In 2003, HE4 was approved by the FDA as a serum tumor marker for ovarian cancer. A HE4 immunohistochemistry study demonstrated staining in all ovarian (36) and endometrioid (10) carcinomas. Recent studies have shown HE4 expression in other malignant tumors including lung adenocarcinoma, stomach cancer and pancreatic cancer.