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.