Salmans Michael L, Zhao Fang, Andersen Bogi
Breast Cancer Res. 2013 Apr 24;15(2):204. doi: 10.1186/bcr3408.
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.
前梯度2（AGR2）最初是在乳腺癌细胞系中作为一种雌激素反应基因被发现的，它是一个受发育调控的基因，属于蛋白质二硫键异构酶（PDI）基因家族。在发育过程中，AGR2以雌激素依赖的方式在乳腺中表达，AGR2基因敲除和过表达小鼠模型表明该基因通过刺激细胞增殖促进小叶腺泡发育。虽然单独的AGR2过表达似乎不足以在小鼠中引发乳腺肿瘤，但多项研究表明AGR2促进乳腺肿瘤发生。在几种乳腺癌细胞系中过表达AGR2可增加克隆形成试验中的细胞存活率和细胞增殖，而AGR2功能丧失则导致细胞周期进程减慢和细胞死亡。此外，在体内转移试验中，AGR2被证明可促进乳腺上皮细胞的转移。作为一种PDI，AGR2被认为参与了减轻内质网应激的未折叠蛋白反应。由于癌症必须克服因蛋白质产生过多而导致的蛋白毒性应激，AGR2可能是被招募来协助蛋白质折叠或降解或两者兼有的众多促生存因子之一。当AGR2分泌时，它在转移性肿瘤细胞的细胞黏附和扩散中发挥作用。在乳腺癌中，AGR2表达与雌激素受体（ER）阳性肿瘤相关；其过表达是预后不良的一个预测指标。AGR2基因是雌激素受体α（ER-α）的直接靶点，ER-α在预后不良的肿瘤中优先结合。芳香化酶抑制剂疗法可降低AGR2表达，而他莫昔芬在ER阳性肿瘤中作为AGR2表达的激动剂，这可能导致他莫昔芬耐药。AGR2在一部分ER阴性肿瘤中也过表达。此外，AGR2表达与转移性乳腺癌细胞的扩散相关，可作为识别循环肿瘤细胞和前哨淋巴结中转移细胞的标志物。总之，AGR2是乳腺癌中一个有前景的药物靶点，可能作为一个有用的预后指标以及乳腺癌转移的标志物。
