Prognostic Impact of AGR3 Protein Expression in Breast Cancer: A Systematic Review and Meta-analysis

 

 Permissions and Reprints

Abstract

Objective To investigate the clinicopathological significance and prognosis of the expression of the anterior gradient 3 (AGR3) protein in women with breast cancer.

Data Sources The PubMed, CINAHL, EMBASE, Scopus, and Web of Science databases were searched for studies published in English and without restrictions regarding the year of publication. The search terms were: breast cancer AND anterior gradient 3 OR AGR3 expression.

Study Selection We included observational or interventional studies, studies on AGR3 protein expression by immunohistochemistry, and studies on invasive breast cancer. Case reports, studies with animals, and reviews were excluded. In total, 4 studies were included, containing 713 cases of breast cancer.

Data Collection Data were extracted on clinicopathological characteristics and survival. A meta-analysis of the prevalence of AGR3 expression was performed according to the clinicopathological characteristics, hazard ratios (HRs), and overall survival and disease-free survival.

Data Synthesis The expression of AGR3 was found in 62% of the cases, and it was associated with histological grade II, positivity of estrogen and progesterone receptors, low expression of ki67, recurrence or distant metastasis, and lumen subtypes. In patients with low and intermediate histological grades, AGR3 expression was associated with worse overall survival (HR: 2.39; 95% confidence interval [95%CI]: 0.628–4.159; p = 0.008) and worse disease-free survival (HR: 3.856; 95%CI: 1.026–6.686; p = 0.008).

Conclusion The AGR3 protein may be a biomarker for the early detection of breast cancer and predict prognosis in luminal subtypes. In addition, in patients with low and intermediate histological grades, AGR3 protein expression may indicate an unfavorable prognosis in relation to survival.

Resumo

Objetivo Investigar o significado clinicopatológico e prognóstico da expressão da proteína anterior gradient 3 (AGR3) em mulheres com câncer de mama.

Fontes de Dados Utilizamos as bases de dados PubMed, CINAHL, EMBASE, Scopus e Web of Science para pesquisar estudos em inglês, sem restrições quanto ao ano de publicação. Os termos buscados foram: breast cancer AND anterior gradient 3 OR AGR3 expression.

Seleção dos Estudos Foram incluídos estudos observacionais ou intervencionais, estudos sobre a expressão da proteína AGR3 por imuno-histoquímica, e estudos sobre câncer de mama invasivo. Excluíram-se relatos de casos, estudos com animais e revisões. Quatro estudos foram selecionados, que continham 713 casos de câncer de mama.

Coleta de Dados Foram extraídos dados relativos a características clinicopatológicas e sobrevida. A metanálise da prevalência da expressão de AGR3 foi realizada conforme as características clinicopatológicas, razões de risco (RRs) e sobrevida global (SG) e sobrevida livre de doença (SLD).

Síntese dos Dados Encontrou-se expressão de AGR3 em 62% dos casos, que se associou com grau histológico II, positividade de receptores de estrogênio e progesterona, baixa expressão de ki67, recorrência ou metástase à distância e subtipos luminais. Em pacientes com graus histológicos baixo e intermediário, a expressão de AGR3 conferiu pior SG (RR: 2,39; intervalo de confiança de 95% [IC95%]: 0,628–4,159; p = 0,008) e pior SLD (RR: 3,856; IC95%: 1,026–6,686; p = 0,008).

Conclusão A AGR3 pode ser um biomarcador para a detecção precoce do câncer de mama e predizer o prognóstico em subtipos luminais. Em graus histológicos baixo e intermediário, a expressão da proteína AGR3 pode indicar um prognóstico desfavorável em relação à sobrevida.

Publication History

Received: 22 November 2022

Accepted: 21 March 2023

Article published online:
09 November 2023

© 2023. Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Revinter Publicações Ltda.
Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

• References

• 1 Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin 2021
  Google Scholar
• 2 Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA. et al. Molecular portraits of human breast tumours. Nature 2000; 406 (6797) 747-752
  CrossrefPubMedGoogle Scholar
• 3 Sørlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A. et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 2003; 100 (14) 8418-8423
  CrossrefPubMedGoogle Scholar
• 4 Riggio AI, Varley KE, Welm AL. The lingering mysteries of metastatic recurrence in breast cancer. Br J Cancer 2021; 124 (01) 13-26
  CrossrefPubMedGoogle Scholar
• 5 Obacz J, Brychtova V, Podhorec J, Fabian P, Dobes P, Vojtesek B, Hrstka R. Anterior gradient protein 3 is associated with less aggressive tumors and better outcome of breast cancer patients. OncoTargets Ther 2015; 8: 1523-1532
  PubMedGoogle Scholar
• 6 King ER, Tung CS, Tsang YTM, Zu Z, Lok TMG, Deavers MT. et al. The anterior gradient homolog 3 (AGR3) gene is associated with differentiation and survival in ovarian cancer. Am J Surg Pathol 2011; 35 (06) 904-912
  CrossrefPubMedGoogle Scholar
• 7 Samanta S, Tamura S, Dubeau L, Mhawech-Fauceglia P, Miyagi Y, Kato H. et al. Expression of protein disulfide isomerase family members correlates with tumor progression and patient survival in ovarian cancer. Oncotarget 2017; 8 (61) 103543-103556
  CrossrefPubMedGoogle Scholar
• 8 Bu H, Schweiger MR, Manke T, Wunderlich A, Timmermann B, Kerick M. et al. Anterior gradient 2 and 3–two prototype androgen-responsive genes transcriptionally upregulated by androgens and by oestrogens in prostate cancer cells. FEBS J 2013; 280 (05) 1249-1266
  CrossrefPubMedGoogle Scholar
• 9 Brychtova V, Zampachova V, Hrstka R, Fabian P, Novak J, Hermanova M, Vojtesek B. Differential expression of anterior gradient protein 3 in intrahepatic cholangiocarcinoma and hepatocellular carcinoma. Exp Mol Pathol 2014; 96 (03) 375-381
  CrossrefPubMedGoogle Scholar
• 10 Fletcher GC, Patel S, Tyson K, Adam PJ, Schenker M, Loader JA. et al. hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumours and interact with metastasis gene C4.4a and dystroglycan. Br J Cancer 2003; 88 (04) 579-585
  CrossrefPubMedGoogle Scholar
• 11 Garczyk S, von Stillfried S, Antonopoulos W, Hartmann A, Schrauder MG, Fasching PA. et al. AGR3 in breast cancer: prognostic impact and suitable serum-based biomarker for early cancer detection. PLoS One 2015; 10 (04) e0122106
  CrossrefPubMedGoogle Scholar
• 12 Jian L, Xie J, Guo S, Yu H, Chen R, Tao K, Yang C. et al. AGR3 promotes estrogen receptor-positive breast cancer cell proliferation in an estrogen-dependent manner. Oncol Lett 2020; 20 (02) 1441-1451
  CrossrefPubMedGoogle Scholar
• 13 Xu Q, Shao Y, Zhang J, Zhang H, Zhao Y, Liu X. et al. Anterior Gradient 3 Promotes Breast Cancer Development and Chemotherapy Response. Cancer Res Treat 2020; 52 (01) 218-245
  CrossrefPubMedGoogle Scholar
• 14 Obacz J, Takacova M, Brychtova V, Dobes P, Pastorekova S, Vojtesek B, Hrstka R. The role of AGR2 and AGR3 in cancer: similar but not identical. Eur J Cell Biol 2015; 94 (3-4): 139-147
  CrossrefPubMedGoogle Scholar
• 15 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6 (07) e1000097
  CrossrefPubMedGoogle Scholar
• 16 Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D. et al. Meta-analysis of Observational Studies in EpidemiologyA Proposal for Reporting. JAMA 2000; 283: 2008-2012
  CrossrefPubMedGoogle Scholar
• 17 Sterne JAC, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M. et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016; 355: i4919
  CrossrefPubMedGoogle Scholar
• 18 Carrasco-Labra A, Brignardello-Petersen R, Santesso N, Neumann I, Mustafa RA, Mbuagbaw L. et al. Improving GRADE evidence tables part 1: a randomized trial shows improved understanding of content in summary of findings tables with a new format. J Clin Epidemiol 2016; 74: 7-18
  CrossrefPubMedGoogle Scholar
• 19 Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J. et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011; 64 (04) 383-394
  CrossrefPubMedGoogle Scholar
• 20 Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J. et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011; 64 (04) 401-406
  CrossrefPubMedGoogle Scholar
• 21 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327 (7414) 557-560
  CrossrefPubMedGoogle Scholar
• 22 Obacz J, Sommerova L, Sicari D, Durech M, Avril T, Iuliano F. et al. Extracellular AGR3 regulates breast cancer cells migration via Src signaling. Oncol Lett 2019; 18 (05) 4449-4456
  PubMedGoogle Scholar