Abstract
Background
Recent data have shown anterior gradient 2 (AGR2) to be a novel oncogene overexpressed in luminal breast cancers. However, many studies only focused on its relationship with treatment resistance, and the clinical relevance of AGR2 has not been widely evaluated.
Methods
AGR2 expression in a cohort of breast cancer was correlated with the clinicopathologic features, biomarker expression, and patient survival.
Results
AGR2 expression correlated with lower grade (p = 0.002) and absence of necrosis (p = 0.001) and was most highly expressed in luminal cancers (p < 0.001). Correspondingly, AGR2 correlated positively with estrogen receptor, progesterone receptor, and androgen receptor (p < 0.001) and negatively with epidermal growth factor receptor (p = 0.002) and CK5/6 (p < 0.001). AGR2 was an independent unfavorable disease-free survival prognostic factor in patients with hormone therapy (hazard ratio 2.537, p = 0.023). Interestingly, it was also an independent adverse disease-free survival prognostic factor in node-positive luminal cancers (hazard ratio 3.381, p = 0.016). AGR2 expression was higher in nodal metastasis than the corresponding primary tumors in luminal cancers (p = 0.023).
Conclusions
The prognostic impact of AGR2 expression could be related to treatment outcome in estrogen receptor–positive breast cancers and/or its metastasis-promoting effects. It could be an important tumor biomarker and negative prognostic factor potentially exploitable in clinical practice.
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References
Benham AM. The protein disulfide isomerase family: key players in health and disease. Antioxid Redox Signal. 2012;16:781–9.
Fletcher GC, Patel S, Tyson K, 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;88:579–85.
Maresh EL, Mah V, Alavi M, et al. Differential expression of anterior gradient gene AGR2 in prostate cancer. BMC Cancer. 2010;10:680.
Park K, Chung YJ, So H, et al. AGR2, a mucinous ovarian cancer marker, promotes cell proliferation and migration. Exp Mol Med. 2011;43:91–100.
Ramachandran V, Arumugam T, Wang H, Logsdon CD. Anterior gradient 2 is expressed and secreted during the development of pancreatic cancer and promotes cancer cell survival. Cancer Res. 2008;68:7811–8.
Pizzi M, Fassan M, Balistreri M, Galligioni A, Rea F, Rugge M. Anterior gradient 2 overexpression in lung adenocarcinoma. Appl Immunohistochem Mol Morphol. 2012;20:31–6.
Wang Z, Hao Y, Lowe AW. The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation. Cancer Res. 2008;68:492–7.
Fritzsche FR, Dahl E, Pahl S, et al. Prognostic relevance of AGR2 expression in breast cancer. Clin Cancer Res. 2006;12:1728–34.
Thompson DA, Weigel RJ. hAG-2, the human homologue of the Xenopus laevis cement gland gene XAG-2, is coexpressed with estrogen receptor in breast cancer cell lines. Biochem Biophys Res Commun. 1998;251:111–6.
Vanderlaag KE, Hudak S, Bald L, et al. Anterior gradient-2 plays a critical role in breast cancer cell growth and survival by modulating cyclin D1, estrogen receptor-alpha and survivin. Breast Cancer Res. 2010;12:R32.
Liu D, Rudland PS, Sibson DR, Platt-Higgins A, Barraclough R. Human homologue of cement gland protein, a novel metastasis inducer associated with breast carcinomas. Cancer Res. 2005;65:3796–805.
Barraclough DL, Platt-Higgins A, de Silva Rudland S, et al. The metastasis-associated anterior gradient 2 protein is correlated with poor survival of breast cancer patients. Am J Pathol. 2009;175:1848–57.
Hrstka R, Brychtova V, Fabian P, Vojtesek B, Svoboda M. AGR2 predicts tamoxifen resistance in postmenopausal breast cancer patients. Dis Markers. 2013;35:207–12.
Hrstka R, Nenutil R, Fourtouna A, et al. The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers. Oncogene. 2010;29:4838–47.
Innes HE, Liu D, Barraclough R, et al. Significance of the metastasis-inducing protein AGR2 for outcome in hormonally treated breast cancer patients. Br J Cancer. 2006;94:1057–65.
Lakhani SR, Ellis IO, Schnitee SJ, Tan PH, van de Vijver MJ, eds. World Health Organisation classification of tumors of the breast. 4th ed. Lyon: IARC Press; 2012.
Ni YB, Tsang JY, Chan SK, Tse GM. A novel morphologic-molecular recurrence predictive model refines traditional prognostic tools for invasive breast carcinoma. Ann Surg Oncol. 2014;21:2928–33.
Tsang JY, Ni YB, Chan SK, et al. Androgen receptor expression shows distinctive significance in ER positive and negative breast cancers. Ann Surg Oncol. 2014;21:2218–28.
Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ. Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer, 2011. Ann Oncol. 2011;22:1736–47.
Zhang JS, Gong A, Cheville JC, Smith DI, Young CY. AGR2, an androgen-inducible secretory protein overexpressed in prostate cancer. Genes Chromosomes Cancer. 2005;43:249–59.
Liao GS, Chou YC, Hsu HM, Dai MS, Yu JC. The prognostic value of lymph node status among breast cancer subtypes. Am J Surg. (In press).
Valladares-Ayerbes M, Diaz-Prado S, Reboredo M, et al. Bioinformatics approach to mRNA markers discovery for detection of circulating tumor cells in patients with gastrointestinal cancer. Cancer Detect Prev. 2008;32:236–50.
Marin-Aguilera M, Mengual L, Ribal MJ, et al. Utility of urothelial mRNA markers in blood for staging and monitoring bladder cancer. Urology. 2012;79:249.e9–15.
da Costa A, Lenze D, Hummel M, Kohn B, Gruber AD, Klopfleisch R. Identification of six potential markers for the detection of circulating canine mammary tumour cells in the peripheral blood identified by microarray analysis. J Comp Pathol. 2012;146:143–51.
Smirnov DA, Zweitzig DR, Foulk BW, et al. Global gene expression profiling of circulating tumor cells. Cancer Res. 2005;65:4993–7.
Hrstka R, Murray E, Brychtova V, Fabian P, Hupp TR, Vojtesek B. Identification of an AKT-dependent signalling pathway that mediates tamoxifen-dependent induction of the pro-metastatic protein anterior gradient-2. Cancer Lett. 2013;333:187–93.
. Mukhopadhyay P, Chakraborty S, Ponnusamy MP, Lakshmanan I, Jain M, Batra SK. Mucins in the pathogenesis of breast cancer: implications in diagnosis, prognosis and therapy. Biochim Biophys Acta. 2011;1815:224–40.
Kufe DW. Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer. 2009;9:874–85.
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Lacambra, M.D., Tsang, J.Y.S., Ni, YB. et al. Anterior Gradient 2 is a Poor Outcome Indicator in Luminal Breast Cancer. Ann Surg Oncol 22, 3489–3496 (2015). https://doi.org/10.1245/s10434-015-4420-8
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DOI: https://doi.org/10.1245/s10434-015-4420-8