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

Salmans ML, Zhao F, Andersen B - Breast Cancer Res. (2013)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

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.

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Mechanisms of AGR2 activation and subsequent cellular effects of AGR2 expression. Green molecules represent activators of AGR2 expression, and red molecules represent inhibitors. Blue proteins represent targets that AGR2 works through to mediate tumor progression, metastasis, drug resistance, invasion, cell survival, and cell proliferation. AREG, amphiregulin; AGR2, anterior gradient 2; C4.4A, LY6/PLAUR domain containing 3; CTSB/D, cathepsin B and cathepsin D; DAG1, dystroglycan 1; EBP1, ErbB3-binding protein 1; EGFR, epidermal growth factor receptor; ER, estrogen receptor, ERet, endoplasmic reticulum; FOXA, forkhead box family members A1 and A2; HSP90, heat-shock protein 90; Tam, tamoxifen; TGF-β, transforming growth factor-beta; YAP1, yes-associated protein 1.
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Figure 3: Mechanisms of AGR2 activation and subsequent cellular effects of AGR2 expression. Green molecules represent activators of AGR2 expression, and red molecules represent inhibitors. Blue proteins represent targets that AGR2 works through to mediate tumor progression, metastasis, drug resistance, invasion, cell survival, and cell proliferation. AREG, amphiregulin; AGR2, anterior gradient 2; C4.4A, LY6/PLAUR domain containing 3; CTSB/D, cathepsin B and cathepsin D; DAG1, dystroglycan 1; EBP1, ErbB3-binding protein 1; EGFR, epidermal growth factor receptor; ER, estrogen receptor, ERet, endoplasmic reticulum; FOXA, forkhead box family members A1 and A2; HSP90, heat-shock protein 90; Tam, tamoxifen; TGF-β, transforming growth factor-beta; YAP1, yes-associated protein 1.

Mentions: Despite the thorough characterization of AGR2 expression in normal development and breast cancer and other adenocarcinomas, the function of AGR2 in these tissues remains poorly understood. However, given the functional domains characterized in the AGR2 protein and its localization to both the endoplasmic reticulum and the extracellular membrane, it is likely that AGR2 has a role in relieving endoplasmic reticulum stress, promoting the dissemination of metastatic tumor cells, and stimulating cell survival and proliferation (Figure 3).


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

Salmans ML, Zhao F, Andersen B - Breast Cancer Res. (2013)

Mechanisms of AGR2 activation and subsequent cellular effects of AGR2 expression. Green molecules represent activators of AGR2 expression, and red molecules represent inhibitors. Blue proteins represent targets that AGR2 works through to mediate tumor progression, metastasis, drug resistance, invasion, cell survival, and cell proliferation. AREG, amphiregulin; AGR2, anterior gradient 2; C4.4A, LY6/PLAUR domain containing 3; CTSB/D, cathepsin B and cathepsin D; DAG1, dystroglycan 1; EBP1, ErbB3-binding protein 1; EGFR, epidermal growth factor receptor; ER, estrogen receptor, ERet, endoplasmic reticulum; FOXA, forkhead box family members A1 and A2; HSP90, heat-shock protein 90; Tam, tamoxifen; TGF-β, transforming growth factor-beta; YAP1, yes-associated protein 1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672732&req=5

Figure 3: Mechanisms of AGR2 activation and subsequent cellular effects of AGR2 expression. Green molecules represent activators of AGR2 expression, and red molecules represent inhibitors. Blue proteins represent targets that AGR2 works through to mediate tumor progression, metastasis, drug resistance, invasion, cell survival, and cell proliferation. AREG, amphiregulin; AGR2, anterior gradient 2; C4.4A, LY6/PLAUR domain containing 3; CTSB/D, cathepsin B and cathepsin D; DAG1, dystroglycan 1; EBP1, ErbB3-binding protein 1; EGFR, epidermal growth factor receptor; ER, estrogen receptor, ERet, endoplasmic reticulum; FOXA, forkhead box family members A1 and A2; HSP90, heat-shock protein 90; Tam, tamoxifen; TGF-β, transforming growth factor-beta; YAP1, yes-associated protein 1.
Mentions: Despite the thorough characterization of AGR2 expression in normal development and breast cancer and other adenocarcinomas, the function of AGR2 in these tissues remains poorly understood. However, given the functional domains characterized in the AGR2 protein and its localization to both the endoplasmic reticulum and the extracellular membrane, it is likely that AGR2 has a role in relieving endoplasmic reticulum stress, promoting the dissemination of metastatic tumor cells, and stimulating cell survival and proliferation (Figure 3).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

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.

Show MeSH
Related in: MedlinePlus