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

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.

Leveraging the Role of the Metastatic Associated Protein Anterior Gradient Homologue 2 in Unfolded Protein Degradation: A Novel Therapeutic Biomarker for Cancer

“…In ovarian-related cancers, the plasma concentration in 46 samples of patients with ovarian cancer and 61 controls were tested for the immunoreactivity of AGR2, and the results revealed significantly high levels of AGR2 in the cancer cases [55]. The upregulation of AGR2 protein was also seen in low-grade endometrial tumors, which were positively associated with a high expression of hormone receptors [56].…”

Extracellular AGR3 regulates breast cancer cells migration via Src signaling

“…We and others have shown similar expression patterns of AGR2 and AGR3 in non-pathological tissue samples as well as carcinomatous ones, including that of breast, liver and ovary (8–11), which suggests their cognate physiological function and role in pathology. Numerous studies have linked AGR2 with pro-tumoral characteristics that promote cancer aggressiveness and pertain to poor prognoses (12–15). Although AGR2 and AGR3 harbor an ER retention signal sequence (KTEL and QSEL, respectively), they were present in extracellular media such as gastrointestinal mucus, blood or urine (16–19).…”

Anterior Gradient Protein 3 and S100 Calcium-Binding Protein P Levels in Different Endometrial Epithelial Compartments May Play an Important Role in Recurrent Pregnancy Failure

“…AGR3 is required for regulation of ciliary beat frequency and may also be involved in the regulation of intracellular calcium in tracheal epithelial cells [ 18 ]. Endometrial expression and the functional relevance of AGR3 is unknown but AGR2, which shows a 71% sequence homology with AGR3, was previously shown to be hormonally regulated in the endometrium [ 19 ]. AGR3 protein was first identified in breast cancer cell lines [ 19 ].…”

“…Endometrial expression and the functional relevance of AGR3 is unknown but AGR2, which shows a 71% sequence homology with AGR3, was previously shown to be hormonally regulated in the endometrium [ 19 ]. AGR3 protein was first identified in breast cancer cell lines [ 19 ]. Since then, it has been found to be highly expressed in many malignant tissue types and upregulated by both androgens and oestrogens in prostate cancer cell lines [ 20 ].…”