The Metastasis-Associated Anterior Gradient 2 Protein Is Correlated with Poor Survival of Breast Cancer Patients

Barraclough, Dong L.; Platt-Higgins, Angela; Rudland, Suzete de Silva; Barraclough, Roger; Winstanley, John; West, Christopher R.; Rudland, Philip S.

doi:10.2353/ajpath.2009.090246

Cited by 71 publications

(95 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increased AGR2 expression has previously been shown to be associated with metastasis and a poor prognosis in breast cancer patients (Barraclough et al 2009), and to correlate with high-grade serous carcinoma and shortened overall survival of ovarian cancer patients (Innes et al 2006). In addition to the tumor-promoting roles of AGR2, tamoxifen-induced AGR2 expression has also been implicated in the development of resistance of tumors against tamoxifen and cisplatin treatments (Hrstka et al 2010).…”

Section: Discussionmentioning

confidence: 99%

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

Kim

Kim²,

Kang³

et al. 2014

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

Biliary tract cancers include cancers of the gallbladder and extrahepatic bile ducts, and its prognosis is poor. The anterior gradient 2 (AGR2) is a protein disulfide isomerase and is highly expressed in various human cancers, such as breast, prostate and pancreas cancers. AGR2 is expressed in normal cholangiocytes and its expression is maintained during biliary carcinogenesis. However, the clinical significance of AGR2 expression in biliary tract cancer has not yet been assessed. Thus, we examined the expression of AGR2 protein in biliary tract tumors using immunohistochemistry and its association with various clinicopathologic parameters. This study included 100 patients who underwent surgery for biliary tract cancers: 46 men and 54 women with a mean and median age of 64.2 and 65.0 years, respectively. AGR2 expression was detected in ductal epithelial cells of the normal biliary tract and in 95% of biliary tract cancer tissues. While the AGR2 expression was not associated with cancer location, patient age, patient sex, degree of regional lymph node metastasis (N-status), or residual status, the AGR2 expression level was decreased with increased tumor size (T-status, p = 0.006) and progression of tumor stage (p = 0.009). Moreover, well-differentiated cancers tended to show higher AGR2 expression than poorly differentiated cancers (p = 0.068); in fact, AGR2 expression was not associated with patient survival (Kaplan-Meier analysis, p = 0.415). Thus, AGR2 is of limited value as a prognostic marker for biliary tract cancer. In conclusion, the expression of AGR2 is decreased with the progression of biliary tract cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Kim

Kim²,

Kang³

et al. 2014

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

show abstract

“…Overall patient survival and the significant pathological prognostic variables over 20 years have been summarized recently. 1 …”

Section: Patients and Specimensmentioning

confidence: 99%

“…1,27,28 These and the malignant epithelial cell lines derived from pleural effusions of breast cancer patients MCF-7, T47D, MDA-MB-157, and MDA-MB-231 were cultured as described 27 ; the MCF-7 and T47D were relatively noninvasive (low invasive), and MDA-MB-157 and MDA-MB-231 were highly invasive (high invasive). 29 MDA-MB-157-FANCD2 was generated by transducing MDA-MB-157 cells with a retroviral supernatant of a wild-type FANCD2 cDNA pMMP construct 30 and subsequent selection in puromycin as previously described.…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

“…These four proteins are S100A4, osteopontin (OPN), AGR2, and S100P. [1][2][3][4] If their expression is coordinated, then markers of the underlying mechanism should be even more highly correlated with patient demise. One possible coordination mechanism is the generation of an unstable genome by failure of a DNA repair pathway or some other protective mechanism.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Significance of the Fanconi Anemia FANCD2 Protein in Sporadic and Metastatic Human Breast Cancer

Rudland

Platt-Higgins

Davies

et al. 2010

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

FANCD2, a pivotal protein in the Fanconi anemia and BRCA pathway/network, is monoubiquitylated in the nucleus in response to DNA damage. This study examines the subcellular location and relationship with prognostic factors and patient survival of FANCD2 in breast cancer. Antibodies to FANCD2 were used to immunocytochemically stain 16 benign and 20 malignant breast specimens as well as 314 primary breast carcinomas to assess its association with subcellular compartment and prognostic factors using Fisher's Exact test or with patient survival over 20 years using Wilcoxon-Gehan statistics. Immunoreactive FANCD2 was found in the nucleus and cytoplasm of all 16 benign tissues, but nuclear staining was lost from a significant 19/20 malignant carcinomas (P < 0.0001). Antibodies to FANCD2 stained the cytoplasm of 196 primary carcinomas, leaving 118 as negatively stained. Negative cytoplasmic staining was significantly associated with positive staining for the metastasis-inducing proteins S100A4, S100P, osteopontin, and AGR2 (P < 0.002). Survival of patients with FANCD2-negative carcinomas was significantly worse (P < 0.0001) than those with positively stained carcinomas, and only 4% were alive at the census date. Multivariate regression analysis identified negative staining for cytoplasmic FANCD2 as the most significant indicator of patient death (P ‫؍‬ 0.001). Thus FANCD2's cytoplasmic loss in the primary carcinomas may allow the selection of cells overexpressing proteins that can induce metastases before surgery. Previous reports have shown that the expression of four proteins that can induce metastasis in experimental rats are highly significantly correlated with each other and separately with early patient death in human breast cancer. These four proteins are S100A4, osteopontin (OPN), AGR2, and S100P.1-4 If their expression is coordinated, then markers of the underlying mechanism should be even more highly correlated with patient demise. One possible coordination mechanism is the generation of an unstable genome by failure of a DNA repair pathway or some other protective mechanism. The majority of familial breast cancer is associated with individuals heterozygous for the BRCA1 or BRCA2 genes that encode proteins important for the repair of DNA double strand breaks and interstrand crosslinks by homologous recombination. 5,6 Biallelic inactivation of BRCA2 results in one form of the cancer-prone syndrome Fanconi anemia (complementation group FA-D1) and the BRCA2/FANCD1 protein operates with 12 other Fanconi anemia (FA) proteins and BRCA1 in a multifaceted response to DNA damage known as the FA/ BRCA tumor suppressor pathway/network. 7-10 Eight of the 13 proteins, together with two FA-associated-proteins, participate in a nuclear core-complex that is required for the monoubiquitylation of FANCD2 and FANCI.

show abstract

“…A more recent study using patients that have only undergone operative breast cancer surgery indicated that high AGR2 expression is linked to poor survival (Barraclough et al, 2009). Therefore, the precise function of these proteins and the mechanisms of their hormonal regulation in breast cancers remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers

et al. 2010

View full text Add to dashboard Cite

Transcriptomic screens in breast cancer cell lines have identified a protein named anterior gradient-2 (AGR2) as a potentially novel oncogene overexpressed in estrogen receptor (ER) positive tumours. As targeting the ER is responsible for major improvements in cure rates and prevention of breast cancers, we have evaluated the prooncogenic function of AGR2 in anti-hormone therapeutic responses. We show that AGR2 expression promotes cancer cell survival in clonogenic assays and increases cell proliferation and viability in a range of cancer cell lines. Chromatin immunoprecipitation and reporter assays indicate that AGR2 is transcriptionally activated by estrogen through ERa. However, we also found that AGR2 expression is elevated rather than inhibited in response to tamoxifen, thus identifying a novel mechanism to account for an agonistic effect of the drug on a specific pro-oncogenic pathway. Consistent with these data, clinical analysis indicates that AGR2 expression is related to treatment failure in ERapositive breast cancers treated with tamoxifen. In contrast, AGR2 is one of the most highly suppressed genes in cancers of responding patients treated with the anti-hormonal drug letrozole. These data indicate that the AGR2 pathway represents a novel pro-oncogenic pathway for evaluation as anti-cancer drug developments, especially therapies that by-pass the agonist effects of tamoxifen.

show abstract

The Metastasis-Associated Anterior Gradient 2 Protein Is Correlated with Poor Survival of Breast Cancer Patients

Cited by 71 publications

References 28 publications

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

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

Significance of the Fanconi Anemia FANCD2 Protein in Sporadic and Metastatic Human Breast Cancer

The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers

Contact Info

Product

Resources

About