Elsevier

Gynecologic Oncology

Volume 122, Issue 1, July 2011, Pages 132-140
Gynecologic Oncology

Inhibin/activin betaE-subunit in uterine endometrioid adenocarcinoma and endometrial cancer cell lines: From immunohistochemistry to clinical testing?

https://doi.org/10.1016/j.ygyno.2011.03.019Get rights and content

Abstract

Objective

Inhibins and activins are important regulators of the female reproductive system and have also been described to be involved in gynecologic cancer development. A new inhibin/activin subunit betaE has been identified, but only limited data on its expression in human uterine adenocarcinomas and endometrial cancer cell lines exist.

Methods

A series of 223 uterine endometrial adenocarcinomas were immunohistochemically analyzed with a specific antibody against the inhibin betaE-subunit. In addition, established endometrial cancer cell lines were analyzed for the synthesis of the inhibin betaE subunit by immunofluorescence and RT-PCR analysis.

Results

In this analysis, the inhibin betaE staining intensity was associated with histological grading along with a significant decrease in cases with ovarian invasion. However, inhibin-betaE did not affect patient survival nor did it constitute an independent prognostic parameter in endometrial adenocarcinoma patients. Additionally, the inhibin/activin betaE-subunit was found to be expressed in the human endometrial carcinoma cell lines HEC1a, HEC1b, Ishikawa, and RL95-2, although the level of expression was found to be highly differing among the cancer cell lines tested.

Conclusion

The isolated analysis of the inhibin betaE subunit might be of minor prognostic value in identifying high-risk patients. However, its differential expression in cancer of different histological differentiation and ovarian metastasis suggests a putative but yet undefined role in endometrial carcinogenesis. Whether this novel and not well studied inhibin subunit has a substantial function in the pathogenesis and malignant transformation of human endometrium is still under investigation.

Research highlights

► The expression of the inhibin betaE subunit is associated with histological grading and ovarian invasion in patients with endometrioid adenocarcinomas. ► Endometrial carcinoma cell lines express highly differing levels of inhibin betaE, representing useful tools for its functional analysis in cancer.

Introduction

Inhibins and activins are dimeric proteins belonging to the transforming growth factor-beta (TGF-β) family [1], [2]. They are primarily produced from the gonads and perform a substantial function in the modulation of FSH production [3], but have been also been detected in endocrine tumors and play important roles in malignant cell transformation [4]. However, the precise function of these glycoproteins is complicated by their involvement as cytokines in the regulation of cell growth and differentiation [5].

Inhibins and activins in humans are hetero- or homodimers that comprise five possible subunits: one α-subunit and four β-subunit isoforms (βA, βB, βC and βE) [1], [2], [6], [7], [8]. The β-subunits can either form activins by homodimerization with a second β-subunit or, alternatively, can form inhibins by heterodimerization with the α-subunit. The extensively studied β-subunits are the βA- and βB-subunits, while two additional β-subunits (named βC and βE) have been cloned recently [6], [7], [8]. However, their precise function and dimerization potential remains to be defined [6], [7], [8].

Although the βE-subunit is predominantly synthesized in hepatocytes [7], [9], it has recently also been detected in human ovary [10], normal and malignant cervical tissue [11], human endometrium [12], and in normal and pathological human placental tissue [7], [13], [27]. The synthesis and expression pattern of inhibin β-subunits in human normal and malignant tissues has attracted considerable interest, since activin signaling might be a promising target for oncologic therapeutic interventions [14].

In a recent study, we demonstrated expression of the novel inhibin βC- and βE-subunits in normal human endometrium and the human endometrial carcinoma cell line Ishikawa [12], [15]. However, the pathophysiological role of these subunits in endometrial carcinogenesis is still unknown. Further, there are only limited data on the expression of the inhibin βE-subunit in malignant human endometrial tissue and its prognostic significance is unclear. Therefore, the present study was designed to determine βE-subunit expression in malignant endometrial tissues and to assess inhibin βE-subunit synthesis in different endometrial cancer cell lines.

Section snippets

Tissue samples

Pathological and surgical records of 223 patients who were operated in the 1st Department of Obstetrics and Gynecology, Ludwig-Maximilians-University Munich between 1990 and 2002 were reviewed for retrospective immunohistochemical cohort analysis. The analyzed patient group has been previously well-characterized [11], [16], [17], [18], [19]. In this evaluation, women with histological types other than endometrioid adenocarcinomas (mucinous adenocarcinoma, serous adenocarcinoma, clear-cell

Clinicopathological characterization

The clinicopathological features of the endometrial carcinomas are summarized in Table 1. The median patient age at the time of diagnosis was 66.05 years (range, 36.18–89.35 years). One hundred and eighty-one (81.2%) and thirteen (5.8%) patients were diagnosed with FIGO stages I and II, respectively, while twenty-one (9.4%) patients had FIGO stage III and eight patients (3.6%) presented with metastatic disease (FIGO IV).

Histological sections were classified according to the World Health

Discussion

Endometrial cancer has become the most frequent gynecologic malignancy in the Western world [36], [37], [38]. Although this type of cancer is diagnosed at an early stage in most cases, the reason is still unclear as to why almost 20% of patients die of their disease [38]. Meanwhile, several prognostic factors such as histological type, histological grade, surgical stage, pelvic lymph node involvement and myometrial invasion have been established [36], [37]. In this analysis

Conflict of interest statement

The authors declare that they have no competing interests.

Acknowledgments

We would like to thank Mrs. S. Schulze, Mrs. C. Kuhn, Mrs. S. Kunze, Mrs. S. Hoffmann, and Prof. Dr. U. Jeschke for their help with endometrial cancer specimens and endometrial cancer cell lines. This study was partially supported by the FöFoLe program of the Ludwig-Maximilians-University, Munich (297/03), the Friedrich-Baur-Institute, Munich, and the Weigland Stipendium Program of the Ludwig-Maximilians-University, Munich for I. Mylonas. A. Brüning and I. Mylonas are supported by the German

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