Oncotarget

Research Papers:

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

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

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Oncotarget. 2018; 9:31459-31472. https://doi.org/10.18632/oncotarget.25838

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Abstract

Areege Kamal1,2, Anthony Valentijn1, Roger Barraclough3, Philip Rudland3, Nihad Rahmatalla2, Pierre Martin-Hirsch4, Helen Stringfellow4, Shandya B. Decruze1,5 and Dharani K. Hapangama1,5

1Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK

2The National Center for Early Detection of Cancer, Oncology Teaching Hospital, Baghdad Medical City, Baghdad, Iraq

3Institute of Integrative Biology, University of Liverpool, Liverpool, UK

4Lancashire Teaching Hospital NHS Trust, Preston, UK

5Liverpool Women’s Hospital NHS Foundation Trust, Liverpool, UK

Correspondence to:

Dharani K. Hapangama, email: dharani@liv.ac.uk

Keywords: endometrial cancer; AGR2; metastasis; hormone regulation

Received: April 18, 2018     Accepted: July 12, 2018     Published: July 31, 2018

ABSTRACT

Background: 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.

Aim: To assess the utility of AGR2 as a prognostic marker in EC.

Methods: AGR2 immunoexpression was evaluated in 163 human endometrial samples. Change in AGR2 mRNA levels in response to oestrogen and dihydrotestosterone was studied in vitro.

Results: Upregulation 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.

Conclusions: AGR2 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.


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