High AGR2 protein is a feature of low grade endometrial cancer cells.

Areege Kamal,Anthony Valentijn,Philip Rudland,Roger Barraclough,Dharani K Hapangama,Nihad Rahmatalla,Pierre Martin-Hirsch,Shandya B Decruze,Helen Stringfellow

doi:10.18632/oncotarget.25838

Areege Kamal, Anthony Valentijn + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.25838

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Abstract

BackgroundBiomarkers for identification of endometrial cancers (ECs) with high risk of recurrence are required to reduce the rising EC-related mortality. AGR2 is a prognostic marker in several hormonally-regulated cancers.AimTo assess the utility of AGR2 as a prognostic marker in EC.MethodsAGR2 immunoexpression was evaluated in 163 human endometrial samples. Change in AGR2 mRNA levels in response to oestrogen and dihydrotestosterone was studied in vitro.ResultsUpregulation of AGR2 (protein and mRNA) was seen in low grade EC, compared to the postmenopausal endometrium (P = 0.013) and to the high-grade EC (P < 0.0001). Elevated AGR2 protein expression-scores were associated with a high expression of estrogen alpha (ERα), progesterone, androgen receptors and early clinical stages. Metastatic lesions maintained higher AGR2 expression relative to matched-primary tumors. High-AGR2 protein levels were associated with better overall survival (P = 0.02) in all ECs, but in highly-ERα-expressing ECs, AGR2 associated with unfavourable patient outcome. Androgen through its receptor, downregulated AGR2 mRNA in the Ishikawa cells.ConclusionsAGR2 is overexpressed in low grade ECs and positively associated with hormone receptors. The association between high AGR2 and progressive disease within the high-ERα-expressing ECs suggests that in this group of patients, AGR2 might be a potential biomarker of poor prognosis.

Highlights

Endometrial cancer (EC) is the most common gynecological cancer in the Western world and the incidence is expected to double by 2025 [1]; endometrial cancers (ECs)-associated mortality is increasing in an era of decreasing cancer-related mortality in many other cancers [2]
AGR2 is the human homologue of Xenopus laevis Anterior Gradient [7], a protein that belongs to the protein disulfide isomerase family (PDI) of endoplasmic reticulumresident proteins [8]
10/12 (83%) of hyperplastic lesions were in the background of EC, they were significantly younger than other EC patients (P = 0.024)

Summary

Introduction

Endometrial cancer (EC) is the most common gynecological cancer in the Western world and the incidence is expected to double by 2025 [1]; EC-associated mortality is increasing in an era of decreasing cancer-related mortality in many other cancers [2]. The recently proposed molecular classification of EC is projected to improve this, after integrating the suggested 4 molecular www.oncotarget.com groups with the existing clinicopathological subgroupings [6]; reliable bio-markers to predict response to therapy or recurrence during follow-up, are still lacking. AGR2 has been reported to be a prognostic marker in several hormonally-regulated cancers such as those of breast [11, 12], prostate [13] and ovary [14], where it is involved in drug resistance [15, 16] and metastatic growth [17]. While many ECs are hormone responsive [23], the pattern of AGR2 expression and its possible role in endometrial carcinogenesis remains to be described. Biomarkers for identification of endometrial cancers (ECs) with high risk of recurrence are required to reduce the rising EC-related mortality. AGR2 is a prognostic marker in several hormonally-regulated cancers

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