Inhibin-alpha, -betaA and -betaB subunits in uterine non-endometrioid carcinomas: Prognostic significance and clinical implications

Abstract

Inhibins, dimeric peptide hormones composed of an alpha-subunit and one of two possible beta-subunits (betaA or betaB), exhibit substantial roles in human reproduction and in endocrine-responsive tumours. However, the prognostic significance and clinical implications of the inhibin-alpha, -betaA and -betaB subunits in uterine non-endometrioid cancers are still quite unclear. A series of 41 uterine non-endometrioid carcinomas were immunohistochemically analysed with monoclonal antibodies against inhibin-subunits. The staining reactions were correlated with several clinicopathological characteristics and clinical outcome. The inhibin-alpha subunit showed a significant association with age although the loss of this subunit did not affect the survival of patients with non-endometrioid carcinomas and did not constitute an independent prognostic parameter. The inhibin-betaA expression was not associated with any of the analysed clinicopathological parameters and did not affect patients’ survival. In contrast, a low betaB-subunit demonstrated a significant better cause-specific survival. Moreover, inhibin-βB did constitute an independent prognostic parameter in uterine non-endometrioid cancer patients. In contrast to inhibin-alpha and -betaA subunits, the inhibin-betaB subunit seems to have a substantial role in the carcinogenesis and pathology of uterine non-endometrioid carcinomas and might be used as a marker to identify high-risk patients and may aid in the selection of patients for a more aggressive adjuvant therapy.

Introduction

Endometrial cancer has become the most frequent gynaecologic malignancy in the Western World.1, 2, 3 An incidence of 15–20 to 100,000 women per year has been estimated with a life time risk to develop this type of cancer being approximately 2.5%.⁴ Meanwhile, several prognostic factors like histological type, histologic grade, surgical stage, pelvic lymph node involvement and myometrial invasion have been established.1, 2

Meanwhile, endometrial cancer has been described as consisting of two different clinicopathological categories with distinct biological and molecular characteristics.2, 5, 6, 7 Type I endometrial cancers are the most common histopathological form, being usually endometrioid adenocarcinomas, well-differentiated with a more favourable outcome compared to endometrial cancer of the second group.1, 2, 3, 4, 5, 6 Contrarily, type II endometrial cancers are often of the non-endometrioid type, poorly differentiated with a poor prognosis.6, 7, 8 These observations lead to the postulation of a dualistic model for the molecular carcinogenesis in endometrial carcinomas,⁷ although common characteristics of these groups of endometrial cancer exist. The carcinogenesis of type I endometrial carcinomas is thought to be due to oestrogenic risk factors,1, 2, 7 demonstrating genetic alterations like mutations in PTEN and K-ras.⁷ Type II cancers more often exhibit p53 mutations,⁹ HER-2/neu amplification¹⁰ and chromosomal instability.⁷

Inhibins and activins are secreted polypeptides, representing a subgroup of the TGF-β superfamily of growth and differentiation factors.11, 12, 13 Inhibins are heterodimers that consist of an α-subunit and one of two possible β-subunits (βA or βB), resulting in the formation of either inhibin A (α–βA) or B (α–βB), respectively. On the contrary, activins are homodimers of β-subunits linked by a disulphide bond, leading to the formation of activin A (βA–βA), activin B (βB–βB) or activin AB (βA–βB).11, 12, 13 The inhibin-subunits have been primarily detected in endocrine tumours¹⁴ and their differential expression has suggested an important role in malignant cell transformation in human endometrium.15, 16, 17

Interestingly, TGF-β has been recognised as a tumour suppressor in premalignant stages of carcinogenesis with an additional dual role as a pro-oncogene in later stages of the disease, leading to metastasis.¹⁸ The tumour suppressive 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.19, 20 Recently, a significantly lower inhibin-α expression in well-differentiated adenocarcinomas compared to normal and hyperplastic endometrial tissue was demonstrated.21, 22 These results also led to the hypothesis that inhibin-α might be a tumour suppressor with crucial functions in endometrial carcinoma development.¹⁶ This assumption is underlined by demonstrating that inhibin-α subunit was an independent prognostic parameter in a large cohort analysis of human endometrial carcinomas.¹⁷ However, the prognostic significance and clinical implications of the inhibin-α, -βA and -βB subunits in non-endometrioid cancers are still quite unclear.