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Anterior gradient protein 2 (AGR2) is an independent prognostic factor in ovarian high-grade serous carcinoma

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Abstract

Ovarian high-grade serous carcinoma (HGSC, type 2 ovarian carcinoma) is a poor prognosis cancer with limited therapeutic options. We aimed to investigate the expression pattern and prognostic potential of the metastasis-promoting protein anterior gradient 2 (AGR2) in primary HGSC. Immunohistochemistry was applied to a cohort of 124 primary HGSCs using tissue microarrays. Additionally, in 48 type 1 carcinomas (low-grade serous (LGSC), endometrioid (EC), clear cell (CCC), and mucinous carcinoma (MC)), AGR2 expression was investigated in an exploratory approach. A strong expression of AGR2 was seen in 15 HGSCs (12.1 %) and was significantly linked to shortened overall survival (OS, p = 0.011) and also for progression-free survival (PFS, p = 0.001) in the setting of adjuvant platinum-based chemotherapy (CTX). Multivariate survival analysis including age, stage, and residual tumor after surgery revealed that AGR2 expression was an independent prognostic marker for OS (p = 0.001) and PFS (p = 0.001) in HGSC. In type 1 carcinomas, AGR2 was significantly increased as compared to HGSC (p = 0.001) and was seen in subsets of all histological types, low-grade serous LGSC, EC, CCC, and MC. In particular, strong diffuse staining was seen in LGSC and MC. There was no association between AGR2 and estrogen receptor expression in ovarian type 1 or type 2 carcinomas. AGR2 expression identifies highly aggressive HGSC with a compromised prognosis for which novel therapeutic options are needed. Our data strongly support the further evaluation of AGR2 as a therapeutic target and a potential marker for response to platinum-based CTX in this tumor entity.

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References

  1. Bast RC Jr, Hennessy B, Mills GB (2009) The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer 9:415–428

    Article  PubMed  CAS  Google Scholar 

  2. Prat J (2012) Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features. Virchows Arch 460:237–249

    Article  PubMed  Google Scholar 

  3. Cancer Genome Atlas Research Network (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474:609–615

    Article  Google Scholar 

  4. Thigpen T, duBois A, McAlpine J, DiSaia P, Fujiwara K, Hoskins W, Kristensen G, Mannel R, Markman M, Pfisterer J, Quinn M, Reed N, Swart AM, Berek J, Colombo N, Freyer G, Gallardo D, Plante M, Poveda A, Rubinstein L, Bacon M, Kitchener H, Stuart GC, Gynecologic Cancer InterGroup (2011) First-line therapy in ovarian cancer trials. Int J Gynecol Cancer 21:756–762

    Article  PubMed  Google Scholar 

  5. Sive HL, Hattori K, Weintraub H (1989) Progressive determination during formation of the anteroposterior axis in Xenopus laevis. Cell 58:171–180

    Article  PubMed  CAS  Google Scholar 

  6. Brychtova V, Vojtesek B, Hrstka R (2011) Anterior gradient 2: a novel player in tumor cell biology. Cancer Lett 304:1–7

    Article  PubMed  CAS  Google Scholar 

  7. Thompson DA, Weigel RJ (1998) 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 251:111–116

    Article  PubMed  CAS  Google Scholar 

  8. Innes HE, Liu D, Barraclough R, Davies MP, O'Neill PA, Platt-Higgins A, deSilva RS, Sibson DR, Rudland PS (2006) Significance of the metastasis-inducing protein AGR2 for outcome in hormonally treated breast cancer patients. Br J Cancer 94:1057–1065

    Article  PubMed  CAS  Google Scholar 

  9. Barraclough DL, Platt-Higgins A, de Silva RS, Barraclough R, WinstanleyJ WCR, Rudland PS (2009) The metastasis-associated anterior gradient 2 protein is correlated with poor survival of breast cancer patients. Am J Pathol 175:1848–1857

    Article  PubMed  CAS  Google Scholar 

  10. Fritzsche FR, Dahl E, Pahl S, Burkhardt M, Luo J, Mayordomo E, Gansukh T, Dankof A, Knuechel R, Denkert C, Winzer KJ, Dietel M, Kristiansen G (2006) Prognostic relevance of AGR2 expression in breast cancer. Clin Cancer Res 12:1728–1734

    Article  PubMed  CAS  Google Scholar 

  11. Hrstka R, Nenutil R, Fourtouna A, Maslon MM, Naughton C, Langdon S, Murray E, Larionov A, Petrakova K, Muller P, Dixon MJ, Hupp TR, Vojtesek B (2010) The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers. Oncogene 29:4838–4847

    Article  PubMed  CAS  Google Scholar 

  12. Kristiansen G, Pilarsky C, Wissmann C, Kaiser S, Bruemmendorf T, Roepcke S, Dahl E, Hinzmann B, Specht T, Pervan J, Stephan C, Loening S, Dietel M, Rosenthal A (2005) Expression profiling of microdissected matched prostate cancer samples revealsCD166/MEMD and CD24 as new prognostic markers for patient survival. J Pathol 205:359–376

    Article  PubMed  CAS  Google Scholar 

  13. Bu H, Bormann S, Schäfer G, Horninger W, Massoner P, Neeb A, Lakshmanan VK, Maddalo D, Nestl A, Sültmann H, Cato AC, Klocker H (2011) The anterior gradient 2 (AGR2) gene is overexpressed in prostate cancer and may be useful as a urine sediment marker for prostate cancer detection. Prostate 71:575–587

    Article  PubMed  CAS  Google Scholar 

  14. Maresh EL, Mah V, Alavi M, Horvath S, Bagryanova L, Liebeskind ES, Knutzen LA, Zhou Y, Chia D, Liu AY, Goodglick L (2010) Differential expression of anterior gradient gene AGR2 in prostate cancer. BMC Cancer 10:680

    Article  PubMed  CAS  Google Scholar 

  15. Fritzsche FR, Dahl E, Dankof A, Burkhardt M, Pahl S, Petersen I, Dietel M, Kristiansen G (2007) Expression of AGR2 in non small cell lung cancer. Histol Histopathol 22:703–708

    PubMed  CAS  Google Scholar 

  16. Dumartin L, Whiteman HJ, Weeks ME, Hariharan D, Dmitrovic B, Iacobuzio-Donahue CA, Brentnall TA, Bronner MP, Feakins RM, Timms JF, Brennan C, Lemoine NR, Crnogorac-Jurcevic T (2011) AGR2 is a novel surface antigen that promotes the dissemination of pancreatic cancer cells through regulation of cathepsins B and D. Cancer Res 71:7091–7102

    Article  PubMed  CAS  Google Scholar 

  17. Vivekanandan P, Micchelli ST, Torbenson M (2009) Anterior gradient-2 is overexpressed by fibrolamellar carcinomas. Hum Pathol 40:293–299

    Article  PubMed  CAS  Google Scholar 

  18. Sinn BV, Darb-Esfahani S, Wirtz RM, Budczies J, Sehouli J, Chekerov R, Dietel M, Denkert C (2011) Evaluation of a hormone receptor-positive ovarian carcinoma subtype with a favourable prognosis by determination of progesterone receptor and oestrogen receptor 1 mRNA expression in formalin-fixed paraffin-embedded tissue. Histopathology 59:918–927

    Article  PubMed  Google Scholar 

  19. Darb-Esfahani S, Wirtz RM, Sinn BV, Budczies J, Noske A, Weichert W, Faggad A, Scharff S, Sehouli J, Oskay-Ozcelik G, Zamagni C, De Iaco P, Martoni A, Dietel M, Denkert C (2009) Estrogen receptor 1 mRNA is a prognostic factor in ovarian carcinoma: determination by kinetic PCR in formalin-fixed paraffin-embedded tissue. Endocr Relat Cancer 16:1229–1239

    Article  PubMed  Google Scholar 

  20. McCluggage WG (2008) My approach to and thoughts on the typing of ovarian carcinomas. J Clin Pathol 61:152–163

    Article  PubMed  CAS  Google Scholar 

  21. Noske A, Weichert W, Niesporek S, Röske A, Buckendahl AC, Koch I, Sehouli J, Dietel M, Denkert C (2008) Expression of the nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 is a prognostic factor in human ovarian cancer. Cancer 112:1733–1743

    Article  PubMed  CAS  Google Scholar 

  22. Marquez RT, Baggerly KA, Patterson AP, Liu J, Broaddus R, Frumovitz M, Atkinson EN, Smith DI, Hartmann L, Fishman D, Berchuck A, Whitaker R, Gershenson DM, Mills GB, Bast RC Jr, Lu KH (2005) Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon. Clin Cancer Res 11:6116–6126

    Article  PubMed  CAS  Google Scholar 

  23. Wamunyokoli FW, Bonome T, Lee JY, Feltmate CM, Welch WR, Radonovich M, Pise-Masison C, Brady J, Hao K, Berkowitz RS, Mok S, Birrer MJ (2006) Expression profiling of mucinous tumors of the ovary identifies genes of clinicopathologic importance. Clin Cancer Res 12:690–700

    Article  PubMed  CAS  Google Scholar 

  24. Rice GE, Edgell TA, Autelitano DJ (2010) Evaluation of midkine and anterior gradient 2 in a multimarker panel for the detection of ovarian cancer. J Exp Clin Cancer Res 29:62

    Article  PubMed  Google Scholar 

  25. Edgell TA, Barraclough DL, Rajic A, Dhulia J, Lewis KJ, Armes JE, Barraclough R, Rudland PS, Rice GE, Autelitano DJ (2010) Increased plasma concentrations of anterior gradient 2 protein are positively associated with ovarian cancer. Clin Sci (Lond) 118:717–725

    Article  CAS  Google Scholar 

  26. Fletcher GC, Patel S, Tyson K, Adam PJ, Schenker M, Loader JA, Daviet L, Legrain P, Parekh R, Harris AL, Terrett JA (2003) 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 88:579–585

    Article  PubMed  CAS  Google Scholar 

  27. Gray TA, Maclaine NJ, Michie CO, Bouchalova P, Murray E, Howie J, Hrstka R, Maslon MM, Nenutil R, Vojtesek B, Langdon S, Hayward L, Gourley C, Hupp TR (2012) Anterior gradient-3: a novel biomarker for ovarian cancer that mediates cisplatin resistance in xenograft models. J Immunol Methods 378:20–32

    Article  PubMed  CAS  Google Scholar 

  28. King ER, Tung CS, Tsang YT, Zu Z, Lok GT, Deavers MT, Malpica A, Wolf JK, LuKH BMJ, Mok SC, Gershenson DM, Wong KK (2011) The anterior gradient homolog 3 (AGR3) gene is associated with differentiation and survival in ovarian cancer. Am J Surg Pathol 35:904–912

    Article  PubMed  Google Scholar 

  29. Zweitzig DR, Smirnov DA, Connelly MC, Terstappen LW, O'Hara SM, Moran E (2007) Physiological stress induces the metastasis marker AGR2 in breast cancer cells. Mol Cell Biochem 306:255–260

    Article  PubMed  CAS  Google Scholar 

  30. Pohler E, Craig AL, Cotton J, Lawrie L, Dillon JF, Ross P, Kernohan N, Hupp TR (2004) The Barrett's antigen anterior gradient-2 silences the p53 transcriptional response to DNA damage. Mol Cell Proteomics 3:534–547

    Article  PubMed  CAS  Google Scholar 

  31. Harris AL (2002) Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47

    Article  PubMed  CAS  Google Scholar 

  32. Liu D, Rudland PS, Sibson DR, Platt-Higgins A, Barraclough R (2005) Human homologue of cement gland protein, a novel metastasis inducer associated with breast carcinomas. Cancer Res 65:3796–3805

    Article  PubMed  CAS  Google Scholar 

  33. Ramachandran V, Arumugam T, Wang H, Logsdon CD (2008) Anterior gradient 2 is expressed and secreted during the development of pancreatic cancer and promotes cancer cell survival. Cancer Res 68:7811–7818

    Article  PubMed  CAS  Google Scholar 

  34. Vanderlaag KE, Hudak S, Bald L, Fayadat-Dilman L, Sathe M, Grein J, Janatpour MJ (2010) 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 12:R32

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Mrs. Petra Wachs for her excellent technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Pathology, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany

    S. Darb-Esfahani, M. Dietel & C. Denkert

  2. Institute of Pathology Enge, Zürich, Switzerland

    F. Fritzsche

  3. Institute of Pathology, Universitätsklinikum Bonn, Bonn, Germany

    G. Kristiansen

  4. Institute of Pathology, Universitätsklinikum Heidelberg, Heidelberg, Germany

    W. Weichert

  5. Department of Gynecology, Charité Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin, Germany

    J. Sehouli & I. Braicu

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  1. S. Darb-Esfahani
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Correspondence to S. Darb-Esfahani.

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Darb-Esfahani, S., Fritzsche, F., Kristiansen, G. et al. Anterior gradient protein 2 (AGR2) is an independent prognostic factor in ovarian high-grade serous carcinoma. Virchows Arch 461, 109–116 (2012). https://doi.org/10.1007/s00428-012-1273-4

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  • DOI: https://doi.org/10.1007/s00428-012-1273-4

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