Abstract
The ANPEP, AZGP1, and SPDEF genes were previously found to be overexpressed in breast compared to ovarian carcinoma effusions. The present study validated this finding in a larger cohort consisting of both primary and metastatic tumors. ANPEP, AZGP1, and SPDEF mRNA expression was investigated in 83 breast carcinomas (57 primary carcinomas and 26 effusions) and 40 ovarian carcinomas (20 primary carcinomas and 20 effusions) using qPCR. ANPEP protein expression was immunohistochemically analyzed in 53 breast carcinoma effusions and patient-matched primary carcinomas (n = 25) and lymph node metastases (n = 16). mRNA and protein levels were studied for association with tumor type and anatomic site, and for clinical role in breast carcinoma. AZGP1 and SPDEF mRNA was overexpressed in breast compared to ovarian carcinoma (both p < 0.001). AZGP1 mRNA was overexpressed in primary breast carcinoma compared to effusions (p < 0.001), with opposite findings for ANPEP (p = 0.044). AZGP1 mRNA expression correlated with positive ER status (p = 0.032) and grade 1 histology (p = 0.011), whereas SPDEF mRNA levels were associated with positive ER (p = 0.002) and PR (p = 0.013) status and tamoxifen treatment (p = 0.004). ANPEP protein expression was higher in breast carcinoma effusions compared to primary tumors and lymph node metastases (both p = 0.001). ANPEP, AZGP1, and SPDEF levels were unrelated to disease-free or overall survival. This is the first study documenting ANPEP, AZGP1, and SPDEF expression in breast carcinoma effusions. AZGP1 and SPDEF may be novel molecular markers for the differentiation of breast from ovarian carcinoma. ANPEP may be involved in breast carcinoma progression in view of its overexpression in effusions compared to solid specimens.
Similar content being viewed by others
References
Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62:10–29
Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108
Davidson B, Firat P, Michael CW (eds) (2011) Serous Effusions. Springer, London
Information, NCBI. ANPEP alanyl (membrane) aminopeptidase [Homo sapiens] 2012; Available from: http://www.ncbi.nlm.nih.gov/gene/290
Wickström M, Larsson R, Nygren P, Gullbo J (2011) Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Sci 102:501–508
Curnis F, Arrigoni G, Sacchi A, Fischetti L, Arap W, Pasqualini R, Corti A (2002) Differential binding of drugs containing the NGR motif to CD13 isoforms in tumor vessels, epithelia, and myeloid cells. Cancer Res 62:867–874
Guzman-Rojas L, Rangel R, Salameh A, Edwards JK, Dondossola E, Kim YG, Saghatelian A, Giordano RJ, Kolonin MG, Staquicini FI, Koivunen E, Sidman RL, Arap W, Pasqualini R (2012) Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment. Proc Natl Acad Sci U S A 109:1637–1642
Information, NCBI. AZGP1 alpha-2-glycoprotein 1, zinc-binding [Homo sapiens] 2012; Available from: http://www.ncbi.nlm.nih.gov/gene/563
Kong B, Michalski CW, Hong X, Valkovskaya N, Rieder S, Abiatari I, Streit S, Erkan M, Esposito I, Friess H, Kleeff J (2010) AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling. Oncogene 29:5146–5158
Hassan MI, Waheed A, Yadav S, Singh TP, Ahmad F (2008) Zinc alpha 2-glycoprotein: a multidisciplinary protein. Mol Cancer Res 6:892–906
Falvella FS, Spinola M, Pignatiello C, Noci S, Conti B, Pastorino U, Carbone A, Dragani TA (2008) AZGP1 mRNA levels in normal human lung tissue correlate with lung cancer disease status. Oncogene 27:1650–1656
Bing C (2011) Lipid mobilization in cachexia: mechanisms and mediators. Curr Opin Support Palliat Care 5:356–360
Huang Y, Li LZ, Zhang CZ, Yi C, Liu LL, Zhou X, Xie GB, Cai MY, Li Y, Yun JP (2012) Decreased expression of zinc-alpha2-glycoprotein in hepatocellular carcinoma associates with poor prognosis. J Transl Med 10:106
Information, NCBI. SPDEF SAM pointed domain containing ets transcription factor [Homo sapiens] 2012; Available from: http://www.ncbi.nlm.nih.gov/gene/25803
Steffan JJ, Koul HK (2011) Prostate derived ETS factor (PDEF): a putative tumor metastasis suppressor. Cancer Lett 310:109–117
Schaefer JS, Sabherwal Y, Shi HY, Sriraman V, Richards J, Minella A, Turner DP, Watson DK, Zhang M (2010) Transcriptional regulation of p21/CIP1 cell cycle inhibitor by PDEF controls cell proliferation and mammary tumor progression. J Biol Chem 285:11258–11269
Findlay VJ, Turner DP, Moussa O, Watson DK (2008) MicroRNA-mediated inhibition of prostate-derived Ets factor messenger RNA translation affects prostate-derived Ets factor regulatory networks in human breast cancer. Cancer Res 68:8499–8506
Davidson B, Stavnes HT, Holth A, Chen X, Yang Y, IeM S, Wang TL (2011) Gene expression signatures differentiate ovarian/peritoneal serous carcinoma from breast carcinoma in effusions. J Cell Mol Med 15:535–544
Langerød A, Zhao H, Borgan Ø, Nesland JM, Bukholm IR, Ikdahl T, Kåresen R, Børresen-Dale AL, Jeffrey SS (2007) TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer. Breast Cancer Res 9:R30
Hetland TE, Nymoen DA, Emilsen E, Kærn J, Tropé CG, Flørenes VA, Davidson B (2012) MGST1 expression in serous ovarian carcinoma differs at various anatomic sites, but is unrelated to chemoresistance or survival. Gynecol Oncol 126:460–465
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT–PCR data by geometric averaging of multiple internal control genes. Genome Biol 3:RESEARCH0034
Canales RD, Luo Y, Willey JC, Austermiller B, Barbacioru CC, Boysen C, Hunkapiller K, Jensen RV, Knight CR, Lee KY, Ma Y, Maqsodi B, Papallo A, Peters EH, Poulter K, Ruppel PL, Samaha RR, Shi L, Yang W, Zhang L, Goodsaid FM (2006) Evaluation of DNA microarray results with quantitative gene expression platforms. Nat Biotechnol 24:1115–1122
Yuan Y et al (2009) Expression of the folate receptor genes FOLR1 and FOLR3 differentiates ovarian carcinoma from breast carcinoma and malignant mesothelioma in serous effusions. Hum Pathol 40:1453–1460
Yuan Y, Nymoen DA, Stavnes HT, Rosnes AK, Bjørang O, Wu C, Nesland JM, Davidson B (2009) Tenascin-X is a novel diagnostic marker of malignant mesothelioma. Am J Surg Pathol 33:1673–1682
Yuan Y, Dong HP, Nymoen DA, Nesland JM, Wu C, Davidson B (2011) PINCH-2 expression in cancers involving serosal effusions using quantitative PCR. Cytopathology 22:22–29
Brenne K, Nymoen DA, Hetland TE, Trope CG, Davidson B (2012) Expression of the Ets transcription factor EHF in serous ovarian carcinoma effusions is a marker of poor survival. Hum Pathol 43:496–505
Bock AJ, Nymoen DA, Brenne K, Kærn J, Davidson B (2012) SCARA3 mRNA is overexpressed in ovarian carcinoma compared with breast carcinoma effusions. Hum Pathol 43:669–674
Brenne K, Nymoen DA, Reuven R, Davidson B (2012) PRAME (Preferentially Expressed Antigen of Melanoma) is a novel marker for differentiating serous carcinoma from malignant mesothelioma. Am J Clin Pathol 137:240–247
Brusegard K, Stavnes HT, Nymoen DA, Flatmark K, Trope' CG, Davidson B (2012) Rab25 is overexpressed in Müllerian serous carcinoma compared to malignant mesothelioma. Virchows Arch 460:193–202
Gao JJ, Gao ZH, Zhao CR, Yuan Y, Cui SX, Zhang XF, Cheng YN, Xu WF, Tang W, Qu XJ (2011) LYP, a novel bestatin derivative, inhibits cell growth and suppresses APN/CD13 activity in human ovarian carcinoma cells more potently than bestatin. Invest New Drugs 29:574–582
Yamashita M, Kajiyama H, Terauchi M, Shibata K, Ino K, Nawa A, Mizutani S, Kikkawa F (2007) Involvement of aminopeptidase N in enhanced chemosensitivity to paclitaxel in ovarian carcinoma in vitro and in vivo. Int J Cancer 120:2243–2250
van Hensbergen Y, Broxterman HJ, Rana S, van Diest PJ, Duyndam MC, Hoekman K, Pinedo HM, Boven E (2004) Reduced growth, increased vascular area, and reduced response to cisplatin in CD13-overexpressing human ovarian cancer xenografts. Clin Cancer Res 10:1180–1191
Ranogajec I, Jakić-Razumović J, Puzović V, Gabrilovac J (2012) Prognostic value of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and aminopeptidase N/CD13 in breast cancer patients. Med Oncol 29:561–569
Bundred NJ, Walker RA, Everington D, White GK, Stewart HJ, Miller WR (1990) Is apocrine differentiation in breast carcinoma of prognostic significance? Br J Cancer 62:113–117
Chaubert P, Hurlimann J (1992) Mammary origin of metastases. Immunohistochemical determination. Arch Pathol Lab Med 116:1181–1188
Dubois V, Delort L, Mishellany F, Jarde T, Billard H, Lequeux C, Damour O, Penault-Llorca F, Vasson MP, Caldefie-Chezet F (2010) Zinc-alpha2-glycoprotein: a new biomarker of breast cancer? Anticancer Res 30:2919–2925
Parris TZ, Danielsson A, Nemes S, Kovács A, Delle U, Fallenius G, Möllerström E, Karlsson P, Helou K (2010) Clinical implications of gene dosage and gene expression patterns in diploid breast carcinoma. Clin Cancer Res 16:3860–3874
Díez-Itza I, Sánchez LM, Allende MT, Vizoso F, Ruibal A, López-Otín C (1993) Zn-alpha 2-glycoprotein levels in breast cancer cytosols and correlation with clinical, histological and biochemical parameters. Eur J Cancer 29A:1256–1260
Ghadersohi A, Sood AK (2001) Prostate epithelium-derived Ets transcription factor mRNA is overexpressed in human breast tumors and is a candidate breast tumor marker and a breast tumor antigen. Clin Cancer Res 7:2731–2738
Bölke E, Orth K, Gerber PA, Lammering G, Mota R, Peiper M, Matuschek C, Budach W, Rusnak E, Shaikh S, Dogan B, Prisack HB, Bojar H (2009) Gene expression of circulating tumour cells in breast cancer patients. Eur J Med Res 14:426–432
Lacroix M (2006) Significance, detection and markers of disseminated breast cancer cells. Endocr Relat Cancer 13:1033–1067
Sood AK, Saxena R, Groth J, Desouki MM, Cheewakriangkrai C, Rodabaugh KJ, Kasyapa CS, Geradts J (2007) Expression characteristics of prostate-derived Ets factor support a role in breast and prostate cancer progression. Hum Pathol 38:1628–1638
Feldman RJ, Sementchenko VI, Gayed M, Fraig MM, Watson DK (2003) Pdef expression in human breast cancer is correlated with invasive potential and altered gene expression. Cancer Res 63:4626–4631
Turcotte S, Forget MA, Beauseigle D, Nassif E, Lapointe R (2007) Prostate-derived Ets transcription factor overexpression is associated with nodal metastasis and hormone receptor positivity in invasive breast cancer. Neoplasia 9:788–796
Ghadersohi A, Pan D, Fayazi Z, Hicks DG, Winston JS, Li F (2007) Prostate-derived Ets transcription factor (PDEF) downregulates survivin expression and inhibits breast cancer cell growth in vitro and xenograft tumor formation in vivo. Breast Cancer Res Treat 102:19–30
Tjensvoll K, Gilje B, Oltedal S, Shammas VF, Kvaløy JT, Heikkilä R, Nordgård O (2009) A small subgroup of operable breast cancer patients with poor prognosis identified by quantitative real-time RT–PCR detection of mammaglobin A and trefoil factor 1 mRNA expression in bone marrow. Breast Cancer Res Treat 116:329–338
Rodabaugh KJ, Mhawech-Fauceglia P, Groth J, Lele S, Sood AK (2007) Prostate-derived Ets factor is overexpressed in serous epithelial ovarian tumors. Int J Gynecol Pathol 26:10–15
Ghadersohi A, Odunsi K, Zhang S, Azrak RG, Bundy BN, Manjili MH, Li F (2008) Prostate-derived Ets transcription factor as a favorable prognostic marker in ovarian cancer patients. Int J Cancer 123:1376–1384
Acknowledgments
This work was supported by the Norwegian Cancer Society and the Research Foundation at the Norwegian Radium Hospital.
Conflict of interest statement
We declare that we have no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Stavnes, H.T., Nymoen, D.A., Langerød, A. et al. AZGP1 and SPDEF mRNA expression differentiates breast carcinoma from ovarian serous carcinoma. Virchows Arch 462, 163–173 (2013). https://doi.org/10.1007/s00428-012-1347-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-012-1347-3