Identification of a Novel Estrogen-Regulated Gene, EIG121, Induced by Hormone Replacement Therapy and Differentially Expressed in Type I and Type II Endometrial Cancer

Abstract

Purpose:The identification of genes and pathways that are affected by estrogenization may shed light on the mechanisms of estrogen action. Here, we describe the expression pattern of a novel estrogen-induced gene, EIG121, in distinct types of endometrial cancer. Experimental Design: EIG121was identified by cDNA microarray analysis of endometrial RNA from women receiving either placebo or estrogen replacement therapy. The expression level of EIG121 was then measured by real-time quantitative reverse transcription-PCR in benign, hyperplastic, and malignant endometrial samples. A polyclonal antibody was used to detect EIG121 protein by immunohistochemistry. Results: In postmenopausal endometrium, estrogen replacement therapy with Premarin and synthetic estrogen sulfate conjugates induced the expression of EIG1212-and 3-fold, respectively. In premenopausal endometrium, the expression of EIG121was higher in the estrogen-dominated proliferative phase than the secretory phase. In endometrial complex, hyperplasia, and endometrioid adenocarcinoma, neoplastic proliferations associated with estrogen excess, the expression of EIG121 was significantly elevated (on average 3.8-fold in hyperplasias and 21-fold in grade 1 tumors). Although the level of EIG121mRNA in grade 3 endometrioid carcinoma was still 3.5-fold of that in benign endometrium, EIG121 expression tended to decline with increasing tumor grade and disease stage. Immunohistochemistry showed faint staining of normal endometrial epithelium, but intense staining of endometrioid tumors. In sharp contrast, EIG121 expression was significantly suppressed in both uterine papillary serous carcinoma and uterine malignant mixed mullerian tumor, two tumors not associated with estrogen exposure, to <5% of the level in benign endometrium. Conclusions: Our results suggest that EIG121is a good endometrial biomarker associated with a hyperestrogenic state and estrogen-related type I endometrial adenocarcinoma.The endometrium, a complex tissue that lines the uterine cavity, is composed of both glandular and stromal elements. Endometrial carcinoma, which arises from the epithelial component, is the most common gynecologic malignancy and accounts for the majority of the estimated 40,880 new cases and 7,310 related deaths from uterine corpus cancer among women in the U.S. in 2005 (1). Clinicopathologic studies have shown that there are two major types of endometrial carcinoma: type I, an estrogen-related, low-grade endometrioid neoplasm that occurs in younger, premenopausal women and is associated with low clinical stage; and the more clinically aggressive type II, which is usually estrogen-independent, shows nonendometrioid histology, and occurs in postmenopausal women (2). Based on the distinctive clinical and histologic features of the two types of endometrial carcinomas, a dualistic model of carcinogenesis has been proposed for type I and type II tumors (3 -5). Type I endometrial carcinomas are thought to develop in response to prolonged and unopposed estrogen stimulation...

Hypomethylation-induced expression of S100A4 in endometrial carcinoma

“…26 Similarly, we have previously reported that Premarin treatment significantly induced the endometrial tissue expression of the novel estrogenregulated gene, EIG121. 7 In contrast, Premarin and depot MPA caused only slight differences in the endometrial tissue expression of S100A4 compared with baseline; these differences were not statistically significant (Figure 3). Similarly, S100A4 expression does not show differential expression in the estrogen-dominant proliferative phase endometrium compared with the progesterone-dominant secretory endometrium (data not shown).…”

“…21 Gene expression was analyzed in human endometrial biopsies from two different clinical trials involving hormonal therapy. In the first group, described previously, 7 healthy, postmenopausal women received Premarin (Wyeth Research), 0.625 mg/ day p.o., for 3 months. In the second group, healthy, premenopausal women received depot medroxyprogesterone acetate (depot MPA; Pharmacia & Upjohn), 150 mg i.m.…”

“…Previous studies have documented interesting molecular differences between endometrioid and nonendometrioid endometrial carcinomas. [5][6][7][8] Metastatic or recurrent endometrial carcinomas represent a significant treatment problem, as current chemotherapeutic and hormonal strategies are entirely ineffective. Our laboratory has a long-term goal of identifying novel molecular events important in advanced endometrial carcinoma, with the ultimate goal of designing rational, targeted therapies for extra-uterine disease.…”

KIAA1324 Suppresses Gastric Cancer Progression by Inhibiting the Oncoprotein GRP78

“…KIAA1324 gene, also known as EIG121 (estrogen-induced gene 121), encodes a 1,013 amino acid (a.a.) transmembrane protein that is highly conserved among species (21). The correlation between KIAA1324 expression and prognosis in endometrial, ovarian, and pancreatic cancer patients was previously reported (21)(22)(23), but the role of KIAA1324 in gastric cancer has not been investigated yet.…”

Paraneoplastic Thrombocytosis in Ovarian Cancer

“…Realtime reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays were performed with whole RNA extracted from tumor specimens (obtained from 46 patients) or liver specimens (from 10 patients and 10 mice) with the use of primer sets specific for human interleukin-6 and murine or human thrombopoietin, respectively, as previously described. 9,14,15 Proliferation index and microvessel density were evaluated by staining for Ki67 and CD31 antigens, respectively. 16,17 Dual immunofluorescence staining for CD31 and desmin and for CD31 and terminal deoxynucleotidyl transferase dUTP biotin nick end labeling (TUNEL) was used to assess pericyte coverage and apoptotic tumor and endothelial cells, respectively.…”