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. 2019 Jul 15;19(1):692.
doi: 10.1186/s12885-019-5857-0.

Impact of uPA/PAI-1 and disseminated cytokeratin-positive cells in breast cancer

Bruno Märkl  1 , Martin Kazik  2   3 , Nadia Harbeck  4 , Elzbieta Jakubowicz  2 , Reinhard Hoffmann  5 , Thomas Jung  6 , Dieter Steinfeld  7 , Gerhard Schenkirsch  8 , Günter Schlimok  9 , Daniel Oruzio  10
Affiliations

Impact of uPA/PAI-1 and disseminated cytokeratin-positive cells in breast cancer

Bruno Märkl et al. BMC Cancer. .

Abstract

Background: The protease uPA and its inhibitor PAI-1 play major roles in hemostasis and are also involved in cancer progression. This is mainly caused by their ability to degrade extracellular matrix-facilitating tumor cell migration. This study aimed to investigate the impact of uPA/PAI-1 and disseminated cytokeratin-positive cells (dCK+) on the outcome and the existence of synergistic effects.

Methods: We retrospectively analyzed a cohort of 480 breast cancer cases with known uPA/PAI-1 and dCK+ status. uPA/PAI-1 was tested on fresh tumor samples using a commercial ELISA test. Bone marrow aspirates were investigated immunocytochemically for CK18.

Results: DCK+ cells were identified in 23% of cases. uPA positivity was significantly associated with the occurrence of dCK+ cells (P = 0.028). uPA and PAI-1 were significantly associated with outcome in the subgroup of early-stage cases without chemotherapy. DCK+ cells alone were not prognostic. However, we found synergistic effects. In the subgroup of node-negative cases with and without chemotherapy, the prognostic impact of uPA and PAI-1 was enhanced in cases with additional dCK-positivity (triple +). In cases without chemotherapy, triple-positive status was independently prognostic (HR: 9.3 CI: 1.1-75) next to T stage.

Conclusions: uPA and PAI-1 seem to influence the metastatic potential of dCK+ cells, which underlines its important role in tumor progression.

Keywords: Breast cancer; Circulating tumor cells; Prognosis; Proteases.

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Conflict of interest statement

B. Märkl received free femtelle™ test kits from the American Diagnostica GmbH and Sekisui Diagnostics GmbH for previous studies. All other authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Immunocytochemically detected disseminated cells a) Three cytokeratin-positive (CK+) single cells; b) A cluster of 13 cytokeratin-positive cells. Note: These stainings were performed without counter-staining; therefore, the nuclei of the tumor cells are visible only as empty spaces within the cells, which explains different amounts of cytokeratin staining
Fig. 2
Fig. 2
Overall survival in node-negative cases. a) Outcome dependent on the occurrence of disseminated cytokeratin-positive cells (dCK+). b) Outcome dependent on the occurrence of dCK+ cells and positivity of the proteases uPA and/or PAI-1 positivity is defined as tissue level above the cut-off. Note: BHST = 0.01
Fig. 3
Fig. 3
Overall survival in node-negative cases without chemotherapy. a) Outcome dependent on the tissue level of uPA BHST = 0.017. b) Outcome dependent on the tissue level of PAI-1 BHST = 0.025. c) Outcome dependent on the occurrence of disseminated cytokeratin positive cells (dCK+). d) Outcome dependent on the occurrence of dCK+ cells and positivity of the proteases uPA and PAI-1 BHST = 0.05
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References

    1. Krebs in Deutschland für 2013/2014. Berlin; 2017.
    1. Tyagi NK, Dhesy-Thind S. Clinical practice guidelines in breast cancer. Curr Oncol. 2018;25(Suppl 1):S151–S160. doi: 10.3747/co.25.3729. - DOI - PMC - PubMed
    1. Nicolini A, Ferrari P, Duffy MJ. Prognostic and predictive biomarkers in breast cancer: past, present and future. Semin Cancer Biol. 2017. - PubMed
    1. Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010;28(1):105–113. doi: 10.1200/JCO.2009.23.7370. - DOI - PubMed
    1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi: 10.1016/j.cell.2011.02.013. - DOI - PubMed