Human Epididymis protein 4 (HE4) is a secreted glycoprotein that overexpresses by serous and endometrioid ovarian carcinomas

Harvard University, Cambridge, Massachusetts, United States
Cancer Research (Impact Factor: 9.33). 04/2005; 65(6):2162-9. DOI: 10.1158/0008-5472.CAN-04-3924
Source: PubMed


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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    • "To date, the cancer antigen 125 (CA125) is the most commonly used tumor marker in the evaluation and clinical management of an ovarian mass, but since it has a low specificity, especially in premenopausal women [13,14], the search for complementary biomarkers is pivotal. Human Epididymis Protein 4 (HE4), a whey-acid protein first isolated in the epithelium of human epididymis and in epithelial cells of the respiratory system as well as in the female reproductive tract [15-17], offers superior specificity in the differentiation of benign and malignant adnexal masses in premenopausal women compared to CA125 [18]. The Risk of Ovarian Malignancy Algorithm (ROMA) was developed by Moore et al. and combines CA125 and HE4 serum levels and the menopausal status of a patient with suspicious pelvic mass, thus stratifying patients into high and low risk groups for having a malignant ovarian lesion [19]. "
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    ABSTRACT: Borderline tumors of the ovary (BOT) are a distinct entity of ovarian tumors, characterized by lack of stromal invasion. Recent studies postulated that the presence of invasive implants, incomplete staging, fertility sparing surgery and residual tumor after surgery are major prognostic factors for BOT. There are no biomarkers that can predict BOT or the presence of invasive implants. The aim of our study was to assess the value of CA125 and HE4 alone, or within ROMA score for detecting BOT, and for predicting the presence of invasive implants. Retrospective, monocentric study on 167 women diagnosed with BOT or benign ovarian masses. Serum HE4, CA125 levels and ROMA were assessed preoperatively. Due to low number of BOT with invasive implants, we performed an unmatched analysis (consecutive patients) and a matched analysis (according to age and histology) to compare BOT with invasive implants, BOT without invasive implants and benign disease. There were no significant differences in the HE4 and CA125 expressions in the three groups of patients (p = 0.984 and p = 0.141, respectively). The ROC analysis showed that CA125 alone is superior to ROMA and HE4 in discriminating patients with BOT with invasive implants from patients with benign diseases and BOT without invasive implants. A newly established score, ROMABOT, did not perform better than ROMA. The analysis of the matched groups revealed similar results as the analysis of all samples. Both HE4 and CA125 are not reliable biomarkers for the diagnosis of BOT or for predicting the presence of invasive implants.
    Journal of Ovarian Research 05/2014; 7(1):49. DOI:10.1186/1757-2215-7-49 · 2.43 Impact Factor
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    • "HE4 (human epididymal secretory protein E4; WAP four-disulphide core domain protein 2) alone or in combination with CA125 [30,31], are the only two biomarkers US FDA approved for monitoring of disease recurrence or progression, but not for screening. Recently, there has been a resurgence of efforts to identify ovarian cancer biomarkers. "
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    ABSTRACT: Ovarian cancer is the most lethal gynecologic disease due to delayed diagnosis, and ascites production is a characteristic of patients in advanced stages. The aim of this study was to perform the proteomic analysis of ascitic fluids of Mexican patients with ovarian carcinoma, in order to detect proteins with a differential expression pattern in the continuing search to identify biomarkers for this disease. Samples were collected from 50 patients from the Instituto Nacional de Cancerologia of Mexico under informed consent and with approval of the bioethics and scientific committees. After elimination of abundant proteins (Albumin/IgGs) samples were processed for 2D electrophoresis and further protein identification by Mass Spectrometry (MALDI-TOF). Molecules of interest were followed by western blot and lectin binding assays, and their tissue location by histo-immunofluorescence and confocal analysis. An area with a differential expression pattern among samples was located in the 2D gels. Identified proteins were 6 alpha 1 isoforms and 1 alpha 2 isoform of Haptoglobin, and 2 isoforms of Transthyretin. While Transthyretin isoforms were constitutively expressed in all samples, clear differences in the expression pattern of Haptoglobin alpha isoforms were found. Moreover, increased levels of fucosylation of Haptoglobin alpha isoforms analyzed in 40 samples by Aleuria aurantia lectin binding by 1D overlay assay showed a positive correlation with advanced stages of the disease. Tissue detection of Haptoglobin and its fucosylated form, by histo-immunofluorescence in biopsies of ovarian cancer, also showed a correlation with ovarian cancer progression. Moreover, results show that fucosylated Haptoglobin is produced by tumor cells. Increased numbers of highly fucosylated Haptoglobin alpha isoforms in ascitic fluids and the presence of fucosylated Haptoglobin in tumor tissues of ovarian cancer Mexican patients associated with advanced stages of the disease, reinforce the potential of fucosylated Haptoglobin alpha isoforms to be characterized as biomarkers for disease progression.
    Journal of Ovarian Research 02/2014; 7(1):27. DOI:10.1186/1757-2215-7-27 · 2.43 Impact Factor
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    • "No expression was found in the germ cell, gonadal tumors and mucinous carcinomas [23]. Drapkin et al. [24] also demonstrated the expression of WFDC2 glycoprotein in inclusion ovarian cysts of the Mullerian origin ovarian cancer, pointing at possible involvement of these lesions in the process of ovarian carcinogenesis. The lack of changes in the HE4 concentrations in serum in the course of a woman’s menstrual cycle indicates a lack of correlation with and dependence on hormones of the menstrual cycle [25,26]. "
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    ABSTRACT: The aim of our study was to evaluate the behaviour of the human epididymis protein 4 (HE4) in the peritoneal fluid encountered in various female genital diseases. We enrolled 139 patients, 40 with ovarian cancer (group I), 82 with benign diseases (group II), and 17 with other malignant neoplasms (group III). The HE4 tumor marker concentrations were determined in serum, in the peritoneal effusion and ovarian cyst/ tumor fluids, CA125 in the serum only. We compared the groups, examined correlations and determined corresponding ROC curves. We evaluated the relationship between the HE4 marker concentration in the peritoneal effusion in the group I, depending on the selected prognostic parameters. The HE4 median value between the study groups did not differ statistically significantly and were as follows: in group I 3322 pmol/L, in the group II 2150 pmol/L and in the group III 627 pmol/L (p = 0.206376 for the groups I and II, p = 0.05929 for the groups I and III and p = 0.0797 for the groups II and III. In group I there were no differences found in the HE4 concentrations in the peritoneal fluid, depending on the stage, grade, the presence of neoplastic cells and the peritoneal dissemination. The HE4 marker concentrations in the peritoneal fluid are highly irrespective of the pathology observed in the female sexual organ. Therefore, it seems that its determinations in the peritoneal fluid are completely useless in terms of diagnostics. More research is needed on the role of the HE4 marker, especially the place of its formation and possible use in the targeted therapy.
    Journal of Ovarian Research 02/2014; 7(1):22. DOI:10.1186/1757-2215-7-22 · 2.43 Impact Factor
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