Expression of metastasis-associated protein 1 (MTA1) in benign endometrium and endometrial adenocarcinomas

Summary

Endometrial carcinoma is one of the most common malignancies of the female genital tract. Metastasis-associated protein 1 (MTA1) is a component of the Mi-2/nucleosome remodeling and deacetylating complex and acts as a potent corepressor of estrogen receptor in breast cancer cells. MTA1 expression has been demonstrated in various cancers but has never been explored in endometrial carcinoma. We investigated the expression profile of MTA1 in different stages of benign endometrium as well as in endometrial endometrioid adenocarcinoma using immunohistochemistry and Western blotting. In the proliferative and secretory phases, MTA1 was expressed in both the glandular and the stromal compartments and was localized in nucleus and cytoplasm of these cells. MTA1 expression in secretory phase was less prominent when compared with the proliferative phase. In postmenopausal sections, MTA1 staining was observed in both glandular and stromal compartments and was localized in both nucleus and cytoplasm. Western blot analysis of 6 tumor specimens showed increased expression of MTA1 in all the tumors analyzed. Immunohistochemical staining performed on tumor microarray containing 70 endometrial endometrioid adenocarcinomas of various grades showed increased expression of MTA1 in 53 (75.7%) tumors. In grade 1 and grade 2 tumors, MTA1 was present in both nucleus and cytoplasm. Interestingly, in grade 3 tumors, MTA1 was localized in the cytoplasm only. Our results suggest a potential role of MTA1 in endometrial carcinomas.

Introduction

Endometrial cancer is the third most common cancer in women and represents a common malignancy of the female genital tract. Endometrial carcinomas are distinguished based on the biology and clinical course into two types, the estrogen-dependent endometrioid carcinomas, which show frequent expression of estrogen and progesterone receptors, and the non–estrogen-dependent papillary serous or clear cell carcinomas [1], [2]. The molecular mechanisms involved in the progression of endometrial cancer remain poorly understood. The endometrium, the lining of the uterus, undergoes proliferation, differentiation, and degeneration in response to steroid hormones [3]. One such steroid hormone is 17β-estradiol (E2), which plays an important role in controlling the expression of genes involved in a wide variety of biologic processes, including reproduction, development, and homeostasis in a wide variety of tissues including bone, breast, uterus, testis, and the cardiovascular system [4]. Unopposed stimulation of the endometrium by estrogens is identified as the major etiological factor involved in the development of endometrial carcinoma [5].

The biologic effects of estrogen are mediated by its binding to the structurally and functionally distinct estrogen receptors (ERs) ERα and ERβ [6], [7]. Binding of E2 to ERs triggers a conformational change, leading to a series of events involved in the transcription of its target genes. The transcriptional activity of the ER is affected by a number of regulatory cofactors including chromatin-remodeling complexes, coactivators, and corepressors [8], [9], [10]. Coactivators usually do not bind to DNA but are recruited to the target gene promoters through protein-protein interactions with the ERs and function as linker molecules between DNA-binding proteins and DNA and protein-modifying enzymes, which facilitate local structural alterations. In contrast, corepressors have been shown to preferentially associate with antagonist-occupied nuclear receptors [8], [9], [10].

The differential action of estrogen in the breast and endometrium is widely believed to be dependent on the tissue-specific expression of the ER isoforms, coregulators, and availability of novel integrators [11], [12]. Emerging data and the identification of novel ER cofactors with diverse functions are beginning to shed light on the complex events involved in the action of ER. Until recently, however, few studies have looked at the expression of several steroid receptor coactivators such as PELP1, SRC1, CBP, and AIB1 and corepressors such as NCOR and SMRT in the benign endometrium and endometrial carcinoma [13], [14], [15], [16]. Because of the increasing awareness of the potential contribution of extranuclear functions of ER, it is also important to examine the status and localization of other emerging novel steroid receptor corepressors to fully understand the mechanisms of E2 signaling in the endometrium.

Metastasis-associated protein 1 (MTA1) was recently identified as a corepressor of ER and plays a role in the growth factor–mediated hormonal independence via recruitment of histone deacetylases to ERs [17]. Up-regulation of MTA1 expression has been reported in various carcinomas such as breast [18], colorectal [19], [20], gastric [20], esophageal [21], [22], pancreatic [23], ovarian [24], non–small cell lung [25], prostate [26], and hepatocellular carcinomas [27]. MTA1 is also up-regulated in thymoma [28]. The present study was designed to study the relative expression and localization of MTA1 in benign endometrial tissues and in endometrial adenocarcinomas by immunohistochemistry.