Abstract
Among the genes most commonly identified in gene expression profiles of epithelial ovarian carcinomas (EOC) is the gene for human epididymis protein 4 (HE4). To ascertain its clinical utility, we did a comprehensive assessment of HE4 protein expression in benign and malignant ovarian and nonovarian tissues by immunohistochemistry. In comparison with normal surface epithelium, which does not express HE4, we found that cortical inclusion cysts lined by metaplastic Mullerian epithelium abundantly express the protein. Its expression in tumors was restricted to certain histologic subtype: 93% of serous and 100% of endometrioid EOCs expressed HE4, whereas only 50% and 0% of clear cell carcinomas and mucinous tumors, respectively, were positive. Tissue microarrays revealed that the majority of nonovarian carcinomas do not express HE4, consistent with our observation that HE4 protein expression is highly restricted in normal tissue to the reproductive tracts and respiratory epithelium. HE4 is predicted to encode a secreted protein. Using reverse transcription-PCR, we identified ovarian cancer cell lines that endogenously overexpress HE4. Cultured medium from these cells revealed a secreted form of HE4 that is N-glycosylated. This observation is consistent with the recent report that HE4 circulates in the bloodstream of patients with EOC. Therefore, HE4 is a secreted glycoprotein that is overexpressed by serous and endometrioid EOCs. Its expression in cortical inclusion cysts suggests that formation of Mullerian epithelium is a prerequisite step in the development of some types of EOCs.
Highlights
Ovarian cancer is a leading cause of cancer-related death of women in the United States
Under conditions where the human epididymis protein 4 (HE4) antibody shows specific immunostaining for HE4 in the epididymis, we found that the expression of the HE4 protein is highly restricted in normal human tissues (Table 1)
We present a comprehensive www.aacrjournals.org analysis of HE4 protein expression in normal and malignant human tissues and show that expression of HE4 protein is highly restricted in normal human tissues and is largely limited to the epithelium of the reproductive tracts and to the respiratory epithelium of the proximal airways
Summary
Ovarian cancer is a leading cause of cancer-related death of women in the United States. It is estimated that in 2004, f24,000 American women will be diagnosed with ovarian cancer and that 14,000 women will die of the disease [1]. At the time of diagnosis, three quarters of patients have locally advanced or disseminated disease that is characterized by diffuse intraperitoneal spread and in many cases, Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org). Cures are rare at advanced clinical stages, placing emphasis on early detection to reduce ovarian cancer mortality. We previously validated the expression of several of the most frequently identified and most highly expressed genes (Mucin, EpCAM, Mesothelin, and CD9) in human ovarian cancer by immunohistochemistry on tumor samples [20]
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