Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometriold ovarian carcinomas

Harvard University, Cambridge, Massachusetts, United States
Cancer Research (Impact Factor: 9.28). 04/2005; 65(6):2162-9. DOI: 10.1158/0008-5472.CAN-04-3924
Source: PubMed

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.

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Available from: Samuel C Mok, Jul 24, 2015
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    • "Loss of tissue expression was observed in serous carcinoma (15%) and endometrioid carcinoma. In contrast, earlier studies reported that HE4 is over expressed in serous and endometrioid carcinoma and not expressed in mucinous carcinoma (Drapkin et al., 2005; Galgano et al., 2006). This could be due to intratumoral variability of staining and probably warrants extensive sampling of the tumour (Galgano et al., 2006). "
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    ABSTRACT: The objective of this study is to assess tissue expression of CA-125 and HE4 protein in primary benign and malignant epithelial tumours of the ovary and correlate with serum CA-125 levels. A total of 100 formalin-fixed, paraffin embedded sections of ovarian tumours which included serous adenoma (11), mucinous adenoma (42), serous carcinoma (20), mucinous carcinoma (12) and endometrioid carcinoma (15), histologically diagnosed between 1st January 2004 to 31st December 2012 at the University Malaya Medical Centre, were stained for HE4 (rabbit polyclonal antibody, Abcam, UK) and CA-125 (mouse monoclonal antibody clone: OC125, Cell Marque Corporation, Rocklin, California, USA). Pre-operative serum CA-125 levels were obtained from the laboratory information system. Immunoscore (I score) for HE4 and CA-125 was given based on the intensity of staining and percentage of positive tumour cells and considered significant when it was >50 (intensity of staining multiplied by percentage of positive tumour cells). Serum CA-125 levels were compared with the I score of HE4 and CA-125 in tissues. We noted that the CA-125 levels in serum and tissues were significantly raised in malignant compared to benign ovarian tumours (p value<0.05). Tissue expression of HE4 protein was also significantly raised in malignant tumours compared to benign tumours (p value<0.05). We conclude that HE4 can be a useful tissue immunomarker in addition to CA-125.
    Asian Pacific journal of cancer prevention: APJCP 08/2013; 14(8):4545-4548. DOI:10.7314/APJCP.2013.14.8.4545 · 2.51 Impact Factor
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    • "Several studies analyzed HE4 protein expression in different tissues, and it was found to be increased in some pulmonary, endometrial, and breast adenocarcinomas, mesotheliomas, and less often, gastrointestinal, renal, and transitional cell carcinomas [10]. Of note, it resulted normally expressed in normal ovarian tissue but overexpressed in ovarian cancers, particularly in the endometrioid histotype [11]. Thanks to the production of two monoclonal antibodies (90.1.6 "
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    ABSTRACT: OBJECTIVE: The quality of first surgery is one of the most important prognostic factors in ovarian cancer patients. Pre-surgical distinction of benign and malignant pelvic mass plays a critical role in ovarian cancer management and survival. The aim of this study was to evaluate the clinical performance of ROMA algorithm and of CA125 and HE4 in the triage of patients with a pelvic mass undergoing surgery, in order to discriminate benign from malignant disease. METHODS: Three hundred and forty-nine pre- and post-menopausal women, aged 18years or older undergoing surgery because of a pelvic mass were enrolled: serum concentrations of CA125 and HE4 were determined and ROMA was calculated for each sample. RESULTS: Median serum CA125 and HE4 levels were higher in patients with EOC compared to subjects with benign disease (p<0.0001). The resultant accuracy (using Receiver Operating Characteristics, ROC Area) values for HE4, CA125 and ROMA showed a good performance ranging from 89.8% for CA125 in pre-menopausal patients to 93.3% for ROMA in post-menopausal patients: AUC for ROMA resulted significantly higher in comparison to CA125 alone (93.3% vs 90.3%, p=0.0018) in post menopausal patients. A sub-analysis considering the 40 patients with endometrioid disease showed the highest accuracy of HE4 in these patients. CONCLUSIONS: Data presented confirm the accuracy of HE4 and of the ROMA algorithm in the distinction of ovarian carcinoma from benign disease, with a trend towards better performance for ROMA than for CA125 alone, statistically significant in postmenopausal patients.
    Gynecologic Oncology 11/2012; 128(2). DOI:10.1016/j.ygyno.2012.11.026 · 3.69 Impact Factor
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    • "These results indicate that the up-regulation of HE4 is associated with tissue-specific carcinogenesis at variable points in neoplastic progression. HE4 is a member of a broader family of secreted putative protease inhibitors, all containing 2 to 4 WAP domains [4] [5] [14]. The exact function of these proteins is poorly understood, but their status as likely extracellular protease inhibitors suggests that they may be involved in the regulation of extracellular matrix, cell migration, and cell invasion. "
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    ABSTRACT: Upper gastrointestinal neoplasia in the esophagus, stomach, and pancreas is associated with the formation of preneoplastic metaplasias. We have previously reported the up-regulation of human epididymis protein 4 (HE4) in all metaplasias in the stomach of humans and mice. We have now sought to evaluate the expression of HE4 in metaplasias/preneoplastic precursors and cancers of the human stomach, pancreas, and esophagus. Tissue microarrays for gastric cancers, pancreatic cancers, and esophageal adenocarcinoma were stained with antibodies against HE4. Immunostaining was quantified by digital imaging, and the results were evaluated to assess the expression in metaplasias, the expression in cancer pathological subtypes, and the effects of expression on survival in patients with cancer. In patients with gastric cancer from Korea, HE4 was detected in 74% of intestinal and 90% of diffuse cancers, whereas in a gastric cancer cohort from Johns Hopkins, HE4 was detected in 74% of intestinal-type and 92% of diffuse cancers. Nevertheless, in both cohorts, there was no impact of HE4 expression on overall survival. In the esophagus, we observed the expression of HE4 in scattered endocrine cells within Barrett esophagus samples, but Barrett columnar metaplasias and HE4 were detected in only 2% of esophageal adenocarcinomas. Finally, in the pancreas, HE4 expression was not observed in pancreatic intraepithelial neoplasia lesions, but 46.8% of pancreatic adenocarcinomas expressed HE4. Still, we did not observe any influence of HE4 expression on survival. The results suggest that HE4 is up-regulated during gastric and pancreatic carcinogenesis.
    Human pathology 10/2012; 44(5). DOI:10.1016/j.humpath.2012.07.017 · 2.81 Impact Factor
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