The estrogen-regulated anterior gradient 2 (AGR2) protein in breast cancer: a potential drug target and biomarker

Abstract

Initially discovered as an estrogen-responsive gene in breast cancer cell lines, anterior gradient 2 (AGR2) is a developmentally regulated gene belonging to the protein disulfide isomerase (PDI) gene family. Developmentally, AGR2 is expressed in the mammary gland in an estrogen-dependent manner, and AGR2 knockout and overexpression mouse models indicate that the gene promotes lobuloalveolar development by stimulating cell proliferation. Although AGR2 overexpression alone seems insufficient for breast tumorigenesis in mice, several lines of investigations suggest that AGR2 promotes breast tumorigenesis. Overexpression of AGR2 in several breast cancer cell lines increases cell survival in clonogenic assays and cell proliferation, whereas AGR2 loss of function leads to decreased cell cycle progression and cell death. In addition, AGR2 was shown to promote metastasis of breast epithelial cells in an in vivo metastasis assay. As a PDI, AGR2 is thought to be involved in the unfolded protein response that alleviates endoplasmic reticulum stress. Since cancer has to overcome proteotoxic stress due to excess protein production, AGR2 may be one of many pro-survival factors recruited to assist in protein folding or degradation or both. When AGR2 is secreted, it plays a role in cellular adhesion and dissemination of metastatic tumor cells. In breast cancer, AGR2 expression is associated with estrogen receptor (ER)-positive tumors; its overexpression is a predictor of poor prognosis. The AGR2 gene is directly targeted by ER-alpha, which is preferentially bound in tumors with poor outcome. Whereas aromatase inhibitor therapy decreases AGR2 expression, tamoxifen acts as an agonist of AGR2 expression in ER-positive tumors, perhaps contributing to tamoxifen resistance. AGR2 is also overexpressed in a subset of ER-negative tumors. Furthermore, AGR2 expression is associated with the dissemination of metastatic breast cancer cells and can be used as a marker to identify circulating tumor cells and metastatic cells in sentinel lymph nodes. In conclusion, AGR2 is a promising drug target in breast cancer and may serve as a useful prognostic indicator as well as a marker of breast cancer metastasis.

Molecular Profiling of Tumor Cells in Cerebrospinal Fluid and Matched Primary Tumors from Metastatic Breast Cancer Patients with Leptomeningeal Carcinomatosis

“…We also observed significant upregulation of other genes in CSFTCs, such as AGR2 (log 10 RQ ¼ 3.53; adj P ¼ 0.0007), TFF3 (log 10 RQ ¼ 3.21; adj P ¼ 0.0007), and GRB7 (log 10 RQ ¼ 2.86; adj P ¼ 0.01; Supplementary Table S3). Overexpression of these genes has been correlated with aggressive cancer biology (20)(21)(22)(23). Although statistical significance was not achieved, MYC (log 10 RQ ¼ 0.85) was upregulated in CSFTCs as compared with leukocytes (Supplementary Table S3).…”

Expression of Anterior Gradient 2 Is Decreased with the Progression of Human Biliary Tract Cancer

“…Since AGR2 is reportedly up-regulated in various types of cancers, its utility as a cancer biomarker and therapeutic target has been investigated by numerous researchers (Brychtova et al 2011;Chevet et al 2013;Salmans et al 2013). Lepreux et al (2011) reported that AGR2 expression was high in normal columnar cholangiocytes and that its expression pattern appeared to be conserved during cholangiocarcinoma development.…”

The sandwich-type aptasensor based on gold nanoparticles/DNA/magnetic beads for detection of cancer biomarker protein AGR2

“…It has been discovered to be overexpressed in many adenocarcinomas. Recent clinical studies have identified AGR2 protein as a potential biomarker of multiple cancers, including breast, prostate, ovarian, intestinal and colon cancers [2][3][4][5][6][7][8][9][10]. Although a number of researchers have developed various AGR2 detection methods in cancers, quantitative analysis is rarely reported and remained more studies for early diagnosis and treatment [11][12][13].…”