Inhibin-alpha subunit is an independent prognostic parameter in human endometrial carcinomas: Analysis of inhibin/activin-alpha, -betaA and -betaB subunits in 302 cases

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Abstract

Inhibins are dimeric glycoproteins, composed of an alpha-subunit (inhibin-α) and one of two possible beta-subunits (βA or βB), with substantial roles in human reproduction and in endocrine-responsive tumours. The aims of this study were to determine the distribution of inhibin-α, -βA and -βB subunits in malignant human endometrial tissue and the assessment of an association with specific clinicopathologic tumour features and clinical outcome. A series of 302 endometrial cancer tissue samples were immunohistochemically analysed with monoclonal antibodies against inhibin subunits. The inhibin-α subunit showed a significant association with histological grading, surgical staging, lymph node status and diabetes in patients with endometrial cancer. Interestingly, loss of inhibin-α expression resulted in a poorer survival of endometrial cancer patients. Additionally, survival analysis demonstrated that inhibin-α immunoreactivity was an independent prognostic factor for progression-free survival, cause-specific survival as well as for overall survival. In contrast, although inhibin-βA- and -βB subunits showed a significant association between endometrial histological subtypes and histological grading, both subunits were not found to be associated with survival in endometrial cancer patients. Therefore, inhibin-α immunostaining might be used as a simple and efficient marker to identify high-risk patients leading to the selection of patients for an aggressive adjuvant therapy.

Introduction

Endometrial cancer is the most frequent gynaecologic genital malignancy in the western world, with an increasing incidence in the industrial nations.1, 2 Traditional prognostic factors are histological type, tumour grade and depth of myometrial invasion. Although endogenous and exogenous sources of unopposed oestrogen increase the risk of endometrial adenocarcinoma, the molecular pathogenesis of endometrial carcinoma remains unclear.1 However, the currently applied diagnostic technology is insufficient to identify endometrial cancer patients with poor prognosis. Therefore, additional immunohistochemistry of specific markers might be a useful alternative to select high-risk patients.3

Inhibins and activins are homologous proteins, sharing common β-subunits, comprising a nine-cysteine distribution pattern similar to the transforming growth factor-beta (TGF-β) family of proteins.4, 5 Inhibins, in contrast to activins, consist of an α-subunit and one of two possible β-subunits (βA or βB). The α-subunit is able to form heterodimers with either βA- or βB-subunit, resulting in the formation of either inhibin A (α-βA) or inhibin B (α-βB), respectively. Activins are homodimers of β-subunits linked by a disulphide bond. Thus, depending on the subunit combination, there are three isoforms of activin, namely activin A (βA–βA), activin B (βB–βB) and activin AB (βA–βB), which were found to be expressed.4, 5

Inhibin has been demonstrated in normal, hyperplastic and malignant human endometrium6, 7, 8, 9, 10, 11, although the precise roles of inhibin subunits remain still unknown. Interestingly, TGF-β has been recognised as a tumour suppressor in pre-malignant stages of carcinogenesis with an additional dual role as a pro-oncogene in the later stages of disease, leading to metastasis.12 The tumour suppressor activity of the inhibin α-subunit was first identified after functional deletion of the inhibin-α gene in male and female mice, resulting in primary gonadal sex cord-stromal tumours.13 We recently demonstrated a higher expression of the inhibin-α, -βA and -βB subunits in hyperplastic endometrial tissue than in adenocarcinomas, suggesting an involvement of these subunits in endometrial pathogenesis.11, 14, 15 Furthermore, determination of the expression pattern of the inhibin-α subunit in human endometrial tissue might be of predominant importance, since the preferred secretion form of inhibin or activin is determined by this subunit.

Therefore, the aims of this study were

  • (a)

    the determination of the expression and tissue distribution pattern of the inhibin-α, -βB and -βB subunits in malignant endometrial tissues;

  • (b)

    the assessment of these subunits as immunohistochemical markers for malignant endometrial adenocarcinoma;

  • (c)

    the assessment of an association of inhibin/activin subunit expression with specific clinicopathologic tumour features and clinical outcome in a large number of endometrial cancer tissues.

Section snippets

Tissue samples

Three hundred and two hysterectomy specimens containing endometrial carcinoma tissue were obtained from the pathological archives of the 1st Department of Obstetrics and Gynaecology – Ludwig-Maximilians-University Munich between the years 1990 and 2002. In a previous study, endometrial specimens until the year 2001 were analysed for the expression of oestrogen receptor alpha (ERα) and beta (ERβ), progesterone receptor A (PR-A) and B (PR-B).41 All haematoxylin and eosin-stained slides were

Clinicopathological characterisation

Of the total amount of 302 endometrial samples, 293 endometrial carcinomas were analysed for the expression of oestrogen receptor alpha (ERα) and beta (ERβ), progesterone receptor A (PR-A) and B (PR-B) in a recent study.41 The median patients’ age of this analysed population at the time of diagnosis was 64.5 years (range 35.5–87.9 years). 225 (74.5%) and 22 (7.3%) patients were diagnosed in FIGO stages I and II, respectively, while 46 (15.2%) patients had FIGO stage III and 9 patients (3%)

Discussion

Although more than 50% of the patients with endometrial carcinoma are diagnosed with FIGO stage I, as many as 20% die of their disease.28 This is an unusual situation, compared to other solid tumours, and may reflect the failure of current diagnostics to identify pre-malignant stages and endometrial cancer patients with a poor prognosis. Several clinical parameters including well-known prognostic factors such as age, advanced surgical stage, advanced histological grading as well as lymph node

Conflict of interest statement

All authors do not have any financial and personal relationships with other people or organisations that influenced inappropriately this work in any way. This study was partially supported by the FöFoLe program of the Ludwig-Maximilians-University Munich (297/03), the Friedrich-Baur-Institute and the Weigland Stipendium Program of the Ludwig-Maximilians-University Munich for I. Mylonas. Dr. I. Mylonas report having received once lecture fees from DSL Inc. (USA) in the year 2005.

Acknowledgements

We would like to thank Mrs. D. Mayr M.D., Ph.D and Mr. F. Willgeroth M.D., Ph.D for their help in conducting this study. Additionally, we would also like to thank Prof. D. Hölzel – Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University Munich and Mr. M. Schmidt of the Munich Tumour Registry for supplying the survival data. This study was partially supported by the FöFoLe program of the Ludwig-Maximilians-University Munich (297/03), the

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    c

    I. Mylonas and S. Worbs contributed equally.

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