Association of increased primary breast tumorAGR2with decreased disease-specific survival

Abstract

ObjectiveTumor expression of Anterior Gradient 2 (AGR2), an endoplasmic reticulum protein disulfide isomerase, was associated with decreased breast cancer survival. We aimed to validate the association of tumor AGR2 mRNA expression with disease-specific survival (DSS) and identify differentially expressed signaling pathways between high and low AGR2 expression tumor groups.MethodsPrimary tumor mRNA expression data from the METABRIC study was used to evaluate AGR2 expression as a prognostic factor for DSS while adjusting for survival-determining confounders using Cox proportional-hazards regression. Differentially expressed genes and signaling pathway differences between high and low AGR2 groups were determined by modular enrichment analyses using DAVID and Ingenuity Pathway Analysis.ResultsIncreased tumor AGR2 mRNA expression was associated with decreased DSS among 1,341 women (per each standard deviation increase of AGR2 expression: HR 1.14, 95% CI: 1.01-1.29, P = 0.03). Pathway analyses supported prior experimental studies showing that estrogen receptor 1 (ESR1) regulated AGR2 expression. Canonical signaling pathways significantly differentially represented between high and low AGR2 groups included those involved in inflammation and immunity.ConclusionIncreased primary tumor AGR2 expression was associated with decreased DSS. Pathway analyses suggested that increased AGR2 was associated with endoplasmic reticular homeostasis, possibly allowing tumor cells to overcome hypoxic stress and meet the increased protein demand of tumorigenesis, thereby preventing unfolded protein response-mediated apoptosis.

LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription

“…Previous studies have demonstrated the oncogenic role of AGR2 in several solid tumors including breast cancer [7, 42, 44, 46]. Increased AGR2 expression was associated with decreased recurrence-free survival [1]. Consistent with RNA-seq data, AGR2 levels was significantly decreased in LINC02273-depleted cells, determined by qPCR and immunoblotting (Fig.…”

Antibody Therapy Targeting Cancer-Specific Cell Surface Antigen AGR2

“…AGR2 is present in prostate cancer cells but absent in the normal luminal cells [10,11]. Similarly, AGR2 expression is detected in various cancers including pancreatic [12], breast [13], lung [14], colorectal [15], oral [16], subsets of ovarian [17], and bladder [18]. What makes AGR2 attractive for cancer therapy besides its ubiquity in solid tumors is its differential subcellular localization between cancer and normal cells [19] as we demonstrated previously for bladder cancer [18].…”

“…In summary, three AGR2 expression patterns have been described in solid tumors: (1) iAGR2 positive for normal urothelial cells, eAGR2 positive for 25% primary tumors [18]; (2) no AGR2 for prostate epithelial cells, eAGR2 positive for >95% primary tumors [10], similar to pancreas [12] and breast [13]; (3) iAGR2 positive for normal bronchial epithelial cells, eAGR2 positive for>95% non-small cell lung tumors [14].…”

A Bayesian Multivariate Mixture Model for Spatial Transcriptomics Data

“…Meanwhile, cluster 2 expresses tumorassociated antigens (TAAs), i.e., substances produced by tumor cells, such as GFRA1 (Bosco et al, 2018) suggesting cluster 2 as a highly tumor invasive region of the tissue sample. Relatedly, cluster 2 expresses high levels of AGR2, which has been associated with poor breast cancer survival (Ann et al, 2018). Taken together, these results point to an interesting interaction taking place in this breast tissue sample between tumor resistant cells in cluster 1 and cancerous cells in cluster 2.…”