Startseite Tissue kallikrein-related peptidase 4 (KLK4), a novel biomarker in triple-negative breast cancer
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Tissue kallikrein-related peptidase 4 (KLK4), a novel biomarker in triple-negative breast cancer

  • Feng Yang , Michaela Aubele , Axel Walch , Eva Gross , Rudolf Napieralski , Shuo Zhao , Nancy Ahmed , Marion Kiechle , Ute Reuning , Julia Dorn , Fred Sweep , Viktor Magdolen EMAIL logo und Manfred Schmitt
Veröffentlicht/Copyright: 28. Juli 2017

Abstract

Triple-negative breast cancer (TNBC), lacking the steroid hormone receptors ER and PR and the oncoprotein HER2, is characterized by its aggressive pattern and insensitivity to endocrine and HER2-directed therapy. Human kallikrein-related peptidases KLK1-15 provide a rich source of serine protease-type biomarkers associated with tumor growth and cancer progression for a variety of malignant diseases. In this study, recombinant KLK4 protein was generated and affinity-purified KLK4-directed polyclonal antibody pAb587 established to allow localization of KLK4 protein expression in tumor cell lines and archived formalin-fixed, paraffin-embedded TNBC tumor tissue specimens. For this, KLK4 protein expression was assessed by immunohistochemistry in primary tumor tissue sections (tissue microarrays) of 188 TNBC patients, mainly treated with anthracycline- or CMF-based polychemotherapy. KLK4 protein is localized in the cytoplasm of tumor and stroma cells. In this patient cohort, elevated stroma cell KLK4 expression, but not tumor cell KLK4 expression, is predictive for poor disease-free survival by univariate analysis (hazard ratio: 2.26, p=0.001) and multivariable analysis (hazard ratio: 2.12, p<0.01). Likewise, univariate analysis revealed a trend for statistical significance of elevated KLK4 stroma cell expression for overall survival of TNBC patients as well.

Acknowledgments

This project was supported by the Wilhelm Sander-Stiftung, Munich, Germany, contract number 2012.028.1 to M.A. and M.S. and 2016.024.1 to M.A., A.W., V.M. and M.S. as well as by the German Research Foundation (DFG), contract number DO 1772/1-1 to J.D.

References

Beaufort, N., Debela, M., Creutzburg, S., Kellermann, J., Bode, W., Schmitt, M., Pidard, D., and Magdolen, V. (2006). Interplay of human tissue kallikrein 4 (hK4) with the plasminogen activation system: hK4 regulates the structure and functions of the urokinase-type plasminogen activator receptor (uPAR). Biol. Chem. 387, 217–222.10.1515/BC.2006.029Suche in Google Scholar PubMed

Bonzanini, M., Morelli, L., Bonandini, E.M., Leonardi, E., Pertile, R., and Dalla Palma, P. (2012). Cytologic features of triple-negative breast carcinoma. Cancer Cytopathol. 120, 401–409.10.1002/cncy.21207Suche in Google Scholar PubMed

Boström, P., Söderström, M., Vahlberg, T., Söderström, K.O., Roberts, P.J., Carpén, O., and Hirsimäki, P. (2011). MMP-1 expression has an independent prognostic value in breast cancer. BMC Cancer 11, 348.10.1186/1471-2407-11-348Suche in Google Scholar PubMed PubMed Central

Canene-Adams, K. (2013). Preparation of formalin-fixed paraffin-embedded tissue for immunohistochemistry. Methods Enzymol 533, 225–233.10.1016/B978-0-12-420067-8.00015-5Suche in Google Scholar PubMed

Carey, L.A., Perou, C.M., Livasy, C.A., Dressler, L.G., Cowan, D., Conway, K., Karaca, G., Troester, M.A., Tse, C.K., Edmiston, S., et al. (2006). Race breast cancer subtypes and survival in the Carolina Breast Cancer Study. J. Am. Med. Assoc. 295, 2492–2502.10.1001/jama.295.21.2492Suche in Google Scholar PubMed

Cheng, D., Kong, H., and Li, Y. (2013). TMPRSS4 as a poor prognostic factor for triple-negative breast cancer. Int. J. Mol. Sci. 14, 14659–14668.10.3390/ijms140714659Suche in Google Scholar PubMed PubMed Central

Cheng, L., Schneider, B.P., and Li, L. (2016). A Bioinformatics approach for precision medicine off-label drug selection among triple negative breast cancer patients. J. Am. Med. Inform. Assoc. 23, 741–749.10.1093/jamia/ocw004Suche in Google Scholar PubMed PubMed Central

Davidson, B., Xi, Z., and Saatcioglu, F. (2007). Kallikrein 4 is expressed in malignant mesothelioma-further evidence for the histogenetic link between mesothelial and epithelial cells. Diagn. Cytopathol. 35, 80–84.10.1002/dc.20588Suche in Google Scholar PubMed

Dawood, S., Broglio, K., Esteva, F.J., Yang, W., Kau, S.W., Islam, R., Albarracin, C., Yu, T.K., Green, M., Hortobagyi, G.N., et al. (2009). Survival among women with triple receptor-negative breast cancer and brain metastases. Ann. Oncol. 20, 621–627.10.1158/0008-5472.SABCS-6077Suche in Google Scholar

Doherty, M., Metcalfe, T., Guardino, E., Peters, E., and Ramage, L. (2016). Precision medicine and oncology: an overview of the opportunities presented by next-generation sequencing and big data and the challenges posed to conventional drug development and regulatory approval pathways. Ann. Oncol. 27, 1644–1646.10.1093/annonc/mdw165Suche in Google Scholar PubMed

Dorn, J., Bayani, J., Yousef, G.M., Yang, F., Magdolen, V., Kiechle, M., Diamandis, E.P., and Schmitt, M. (2013). Clinical utility of kallikrein-related peptidases (KLK) in urogenital malignancies. Thromb. Haemost. 110, 408–422.10.1160/TH13-03-0206Suche in Google Scholar

Dorn, J., Beaufort, N., Schmitt, M., Diamandis, E.P., Goettig, P., and Magdolen, V. (2014). Function and clinical relevance of kallikrein-related peptidases and other serine proteases in gynecological cancers. Crit. Rev. Clin. Lab. Sci. 51, 63–84.10.3109/10408363.2013.865701Suche in Google Scholar

Duffy, M.J., McGowan, P.M., Harbeck, N., Thomssen, C., and Schmitt, M. (2014). uPA and PAI-1 as biomarkers in breast cancer: validated for clinical use in level-of-evidence-1 studies. Breast Cancer Res. 16, 428.10.1186/s13058-014-0428-4Suche in Google Scholar

Duffy, M.J., Sturgeon, C.M., Sölétormos, G., Barak, V., Molina, R., Hayes, D.F., Diamandis, E.P., and Bossuyt P.M. (2015). Validation of new cancer biomarkers: a position statement from the European group on tumor markers. Clin. Chem. 61, 809–820.10.1373/clinchem.2015.239863Suche in Google Scholar

Erban, J.K., Smith, B.L., Taghian, A.G., editors. (2010). Breast cancer: a multidisciplinary approach to diagnosis and management (New York, USA: Demos Medical Publishing), p. 132.Suche in Google Scholar

Foulkes, W.D., Brunet, J.S., Stefansson, I.M., Straume, O., Chappuis, P.O., Bégin, L.R., Hamel, N., Goffin, J.R., Wong, N., Trudel, M., et al. (2004). The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res. 64, 830–835.10.1158/0008-5472.CAN-03-2970Suche in Google Scholar

Foulkes, W.D., Smith, I.E., and Reis-Filho, J.S. (2010). Triple-negative breast cancer. N. Engl. J. Med. 363, 1938–1948.10.1056/NEJMra1001389Suche in Google Scholar

Frenette, G., Tremblay, R.R., Lazure, C., and Dube, J.Y. (1997). Prostatic kallikrein hK2 but not prostate-specific antigen (hK3) activates single-chain urokinase-type activator. Int. J. Cancer 71, 897–899.10.1002/(SICI)1097-0215(19970529)71:5<897::AID-IJC31>3.0.CO;2-2Suche in Google Scholar

Geyer, F.C., Marchio, C., and Reis-Filho, J.S. (2009). The role of molecular analysis in breast cancer. Pathology 41, 77–88.10.1080/00313020802563536Suche in Google Scholar

Grismayer, B., Sölch, S., Seubert, B., Kirchner, T., Schäfer, S., Baretton, G., Schmitt, M., Luther, T., Krüger, A., Kotzsch, M., et al. (2012). Rab31 expression levels modulate tumor-relevant characteristics of breast cancer cells. Mol. Cancer 11, 62.10.1186/1476-4598-11-62Suche in Google Scholar

Győrffy, B., Bottai, G., Fleischer, T., Munkácsy, G., Budczies, J., Paladini, L, Børresen-Dale, A.L., Kristensen, V.N., and Santarpia, L. (2016). Aberrant DNA methylation impacts gene expression and prognosis in breast cancer subtypes. Int. J. Cancer 138, 87–97.10.1002/ijc.29684Suche in Google Scholar

Harbeck, N., Salem, M., Nitz, U., Gluz, O., and Liedtke, C. (2010). Personalized treatment of early-stage breast cancer: present concepts and future directions. Cancer Treat. Rev. 36, 584–594.10.1016/j.ctrv.2010.04.007Suche in Google Scholar PubMed

Harbeck, N., Schmitt, M., Meisner, C., Friedel, C., Untch, M., Schmidt, M., Sweep, C.G., Lisboa, B.W., Lux, M..P, Beck, T., et al. (2013). Ten-year analysis of the prospective multicentre Chemo-N0 trial validates American Society of Clinical Oncology (ASCO)-recommended biomarkers uPA and PAI-1 for therapy decision making in node-negative breast cancer patients. Eur. J. Cancer 49, 1825–1835.10.1016/j.ejca.2013.01.007Suche in Google Scholar PubMed

Harris, L.N., Ismaila, N., McShane, L.M., André, F., Collyar, D.E., Gonzalez-Angulo, A.M., Hammond, E.H., Kuderer, N.M., Liu, M.C., Mennel, R.G., et al. (2016). American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 34, 1134–1150.10.1200/JCO.2015.65.2289Suche in Google Scholar PubMed PubMed Central

Hassey Dow, K. (2004). Hormonal therapy. In: Contemporary issues in breast cancer: a nursing perspective. (Sidney: Jones and Bartlett Publishers), p. 146.Suche in Google Scholar

Huang, L., Liu, Z., Chen, S., Liu, Y., and Shao, Z. (2013). A prognostic model for triple-negative breast cancer patients based on node status, cathepsin-D and Ki-67 index. PLoS One. 8, e83081.10.1371/journal.pone.0083081Suche in Google Scholar PubMed PubMed Central

Joensuu, H. and Gligoro, J. (2012). Adjuvant treatments for triple-negative breast cancers. Ann. Oncol. 23 (Suppl. 6), vi40–vi45.10.1093/annonc/mds194Suche in Google Scholar PubMed

Kalimutho, M., Parsons, K., Mittal, D., López, J.A., Srihari, S., and Khanna K.K. (2015). Targeted therapies for triple-negative breast cancer: combating a stubborn disease. Trends Pharmacol. Sci. 36, 822–846.10.1016/j.tips.2015.08.009Suche in Google Scholar PubMed

Krishnamurthy, S., Poornima, R., Challa, V.R., and Goud, Y.G. (2012). Triple negative breast cancer-our experience and review. Indian J. Surg. Oncol. 3, 12–16.10.1007/s13193-012-0138-2Suche in Google Scholar PubMed PubMed Central

Lai, J, Myers, S.A., Lawrence, M.G., Odorico, D.M., and Clements, J.A. (2009). Direct progesterone receptor and indirect and rogen receptor interactions with the kallikrein-related peptidase 4 gene promoter in breast and prostate cancer. Mol. Cancer Res. 7, 129–141.10.1158/1541-7786.MCR-08-0218Suche in Google Scholar PubMed

Mangé, A., Desmetz, C., Berthes, M.L., Maudelonde, T., and Solassol, J. (2008). Specific increase of human kallikrein 4 mRNA and protein levels in breast cancer stromal cells. Biochem. Biophys. Res. Commun. 375, 107–112.10.1016/j.bbrc.2008.07.138Suche in Google Scholar PubMed

Marmé, F. and Schneeweiss, A. (2015). Targeted Therapies in triple-negative breast cancer. Breast Care 10, 159–166.10.1159/000433622Suche in Google Scholar PubMed PubMed Central

Michaelidou, K., Ardavanis, A., and Scorilas, A. (2015). Clinical relevance of the deregulated kallikrein-related peptidase 8 mRNA expression in breast cancer: a novel independent indicator of disease-free survival. Breast Cancer Res. Treat. 152, 323–336.10.1007/s10549-015-3470-8Suche in Google Scholar PubMed

Mize, G.J., Wang, W., and Takayama, T.K. (2008). Prostate-specific kallikreins-2 and -4 enhance the proliferation of DU-145 prostate cancer cells through protease-activated receptors-1 and -2. Mol. Cancer Res. 6, 1043–1051.10.1158/1541-7786.MCR-08-0096Suche in Google Scholar PubMed

Mullooly, M., McGowan, P.M., Kennedy, S.A., Madden, S.F., Crown, J., O’ Donovan, N., and Duffy, M.J. (2015). ADAM10: a new player in breast cancer progression? Br. J. Cancer 113, 945–951.10.1038/bjc.2015.288Suche in Google Scholar PubMed PubMed Central

Nelson, P.S., Gan, L., Ferguson, C., Moss, P., Gelinas, R., Hood, L., and Wang, K. (1999). Molecular cloning and characterization of prostase, an and rogen-regulated serine protease with prostate-restricted expression. Proc. Natl. Acad. Sci. USA 96, 3114–3119.10.1073/pnas.96.6.3114Suche in Google Scholar PubMed PubMed Central

Neve, R.M., Chin, K., Fridlyand, J., Yeh, J., Baehner, F.L., Fevr, T., Clark, L., Bayani, N., Coppe, J.P., Tong, F., et al. (2006). A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 10, 515–527.10.1016/j.ccr.2006.10.008Suche in Google Scholar PubMed PubMed Central

Obiezu, C.V., Shan, S.J., Soosaipillai, A., Luo, L.Y., Grass, L., Sotiropoulou, G., Petraki, C.D., Papanastasiou, P.A., Levesque, M.A., and Diamandis, E.P. (2005). Human kallikrein 4: quantitative study in tissues and evidence for its secretion into biological fluids. Clin. Chem. 51, 1432–1442.10.1373/clinchem.2005.049692Suche in Google Scholar PubMed

Pal, A. and Donato, N.J. (2014). Ubiquitin-specific proteases as therapeutic targets for the treatment of breast cancer. Breast Cancer Res. 16, 461.10.1186/s13058-014-0461-3Suche in Google Scholar PubMed PubMed Central

Papachristopoulou, G., Avgeris, M., and Scorilas, A. (2009). Expression analysis and study of KLK4 in benign and malignant breast tumours. Thromb. Haemost. 101, 381–387.10.1160/TH08-01-0037Suche in Google Scholar

Perou, C.M., Sørlie, T., Eisen, M.B., van de Rijn, M., Jeffrey, S.S., Rees, C.A., Pollack, J.R., Ross, D.T., Johnsen, H., Akslen, L.A., et al. (2000). Molecular portraits of human breast tumours. Nature 406 (6797), 747–752.10.1038/35021093Suche in Google Scholar PubMed

Place, A.E., Jin Huh, S., and Polyak, K. (2011). The microenvironment in breast cancer progression: biology and implications for treatment. Breast Cancer Res. 13, 227.10.1186/bcr2912Suche in Google Scholar PubMed PubMed Central

Prassas, I., Eissa, A., Poda, G., and Diamandis, E.P. (2015). Unleashing the therapeutic potential of human kallikrein-related serine proteases. Nat. Rev. Drug Discov. 14, 183–202.10.1038/nrd4534Suche in Google Scholar PubMed

Prat, A., Parker, J.S., Karginova, O., Fan, C., Livasy, C., Herschkowitz, J.I., He, X., and Perou, C.M. (2010). Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 12, R68.10.1186/bcr2635Suche in Google Scholar PubMed PubMed Central

Radisky, E.S. and Radisky, D.C. (2015). Matrix metalloproteinases as breast cancer drivers and therapeutic targets. Front Biosci. 20, 1144–1163.10.2741/4364Suche in Google Scholar PubMed PubMed Central

Rakha, E.A., Reis-Filho, J.S., Baehner, F., Dabbs, D.J., Decker, T., Eusebi, V., Fox, SB., Ichihara, S., Jacquemier, J., Lakhani, S.R., et al. (2010). Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res. 12, 207.10.1186/bcr2607Suche in Google Scholar PubMed PubMed Central

Ramsay, A.J., Dong, Y., Hunt, M.L., Linn, M., Samaratunga, H., Clements, J.A., and Hooper, J.D. (2008). Kallikrein-related peptidase 4 (KLK4) initiates intracellular signaling via protease-activated receptors (PARs) KLK4 and PAR-2 are co-expressed during prostate cancer progression. J. Biol. Chem. 283, 12293–12304.10.1074/jbc.M709493200Suche in Google Scholar PubMed

Reisfeld, R.A. (2013). The tumor microenvironment: a target for combination therapy of breast cancer. Crit. Rev. Oncog. 18, 115–133.10.1615/CritRevOncog.v18.i1-2.70Suche in Google Scholar PubMed

Remmele, W. and Stegner, H.E. (1987). Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8, 138–140.Suche in Google Scholar

Rodríguez-Pinilla, S.M., Sarrió, D., Honrado, E., Moreno-Bueno, G., Hardisson, D., Calero, F., Benítez, J., and Palacios, J. (2007). Vimentin and laminin expression is associated with basal-like phenotype in both sporadic and BRCA1-associated breast carcinomas. J. Clin. Pathol. 60, 1006–1012.10.1136/jcp.2006.042143Suche in Google Scholar PubMed PubMed Central

Schmitt, M., Dorn, J., Kiechle, M., Diamandis, E.P., and Luo, L-Y. (2012). Clinical relevance of kallikrein-related peptidases in breast cancer. In: Kallikrein-related Peptidases. V. Magdolen, C. Sommerhoff, H. Fritz, M. Schmitt, eds. (Berlin, Germany: De Gruyter), pp. 111–144.10.1515/9783110303667.111Suche in Google Scholar

Schmitt, M., Magdolen, V., Yang, F., Kiechle, M., Bayani, J., Yousef, G.M., Scorilas, A., Diamandis, E.P., and Dorn, J. (2013). Emerging clinical importance of the cancer biomarkers kallikrein-related peptidases (KLK) in female and male reproductive organ malignancies. Radiol. Oncol. 47, 319–329.10.2478/raon-2013-0053Suche in Google Scholar PubMed PubMed Central

Seiz, L, Kotzsch, M, Grebenchtchikov, NI, Geurts-Moespot, AJ, Fuessel, S, Goettig, P, Gkazepis, A, Wirth, MP, Schmitt, M, Lossnitzer, A, et al. (2010). Polyclonal antibodies against kallikrein-related peptidase 4 (KLK4): immunohistochemical assessment of KLK4 expression in healthy tissues and prostate cancer. Biol. Chem. 391, 391–401.10.1515/bc.2010.033Suche in Google Scholar

Shaw, J.L.V. and Diamandis, E.P. (2007). Distribution of 15 human kallikreins in tissues and biological fluids. Clin. Chem. 53, 1423–1432.10.1373/clinchem.2007.088104Suche in Google Scholar PubMed

Sidiropoulos K.G., Ding Q., Pampalakis G., White N.M., Boulos P., Sotiropoulou G., and Yousef G.M. (2016). KLK6-regulated miRNA networks activate oncogenic pathways in breast cancer subtypes. Mol. Oncol. 7, 993–1007.10.1016/j.molonc.2016.03.008Suche in Google Scholar PubMed PubMed Central

Simmer, J.P., Fukae, M., Tanabe, T., Yamakoshi, Y., Uchida, T., Xue, J., Margolis, H.C., Shimizu, M., DeHart, B.C., Hu, C.C., et al. (1998). Purification, characterization, and cloning of enamel matrix serine proteinase 1. J. Dent. Res. 77, 377–386.10.1177/00220345980770020601Suche in Google Scholar PubMed

Simmer, J.P., Hu, Y., Lertlam, R., Yamakoshi, Y., and Hu, J.C. (2009). Hypomaturation enamel defects in KLK4 knockout/LacZ knockin mice. J. Biol. Chem. 284, 19110–21.10.1074/jbc.M109.013623Suche in Google Scholar PubMed PubMed Central

Takayama, T.K., McMullen, B.A., Nelson, P.S., Matsumura, M., and Fujikawa, K. (2001). Characterization of hK4 (prostase) a prostate-specificserine protease: activation of the precursor of prostate specific antigen (pro-PSA) and single-chain urokinase type plasminogen activator and degradation of prostatic acid phosphatase. Biochemistry 40, 15341–15348.10.1021/bi015775eSuche in Google Scholar PubMed

The Cancer Degradome (2008). Proteases and Cancer Biology. D. Edwards, G. Hoyer-Hansen, F. Blasi and B.F. Sloane, eds. (New York: Springer Science).Suche in Google Scholar

Tuhkanen, H., Hartikainen, J.M., Soini, Y., Velasco, G., Sironen, R., Nykopp, T.K., Kataja, V., Eskelinen, M., Kosma, V.M., and Mannermaa, A. (2013). Matriptase-2 gene (TMPRSS6) variants associate with breast cancer survival, and reduced expression is related to triple-negative breast cancer. Int. J. Cancer 133, 2334–2340.10.1002/ijc.28254Suche in Google Scholar PubMed

Wahba, H.A. and El-Hadaad, H.A. (2015). Current approaches in treatment of triple-negative breast cancer. Cancer Biol. Med. 12, 106–116.Suche in Google Scholar

Yadav, B.S., Chanana, P., and Jhamb, S. (2015). Biomarkers in triple negative breast cancer: a review. World J. Clin. Oncol. 6, 252–263.10.5306/wjco.v6.i6.252Suche in Google Scholar PubMed PubMed Central

Yang, F., Li, J.Y., Yin, Q.N., Yang, K., Dong, S.N., Bai, L.J., Liu,.P., and Tong, X.W. (2015). Human kallikrein 5 as a novel prognostic biomarker for triple-negative breast cancer: tissue expression analysis and relationship with disease course. Genet Mol. Res. 14, 9655–9666.10.4238/2015.August.14.28Suche in Google Scholar PubMed

Yousef, G.M., Obiezu C.V., Luo, L.-Y., Black M.H., and Diamandes E.P. (1999). Prostase/KLK-L1 is a new member of the human kallikrein gene family, is expressed in prostate and breast tissues, and is hormonally regulated. Cancer Res. 59, 4252–4256.Suche in Google Scholar

Yu, K.H. and Snyder, M. (2016). Omics profiling in precision oncology. Mol. Cell. Proteomics 15, 2525–2536.10.1074/mcp.O116.059253Suche in Google Scholar PubMed PubMed Central

Zardavas, D. and Piccart-Gebhart, M. (2015). Clinical trials of precision medicine through molecular profiling: focus on breast cancer. Am. Soc. Clin. Oncol. Educ. Book 2015, e183–e190.10.14694/EdBook_AM.2015.35.e183Suche in Google Scholar PubMed

Received: 2017-3-2
Accepted: 2017-4-12
Published Online: 2017-7-28
Published in Print: 2017-9-26

©2017 Walter de Gruyter GmbH, Berlin/Boston

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