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Transforming Growth Factor-Beta Signaling Leads to uPA/PAI-1 Activation and Metastasis: A Study on Human Breast Cancer Tissues

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Pathology & Oncology Research

Abstract

Metastasis represents a major problem in the treatment of patients with advanced primary breast cancer. Both Transforming Growth Factor-Beta (TGF-β) signaling and Plasminogen Activator (PA) components, urokinase-type Plasminogen Activator (uPA) and Plasminogen Activator Inhibitor-1 (PAI-1) represent a complex network crucial for such enhanced invasiveness of tumors and imply high prognostic/predictive and promising therapeutic potential. Therefore, protein expression of specific effector molecules comprising the main parts of the TGF-β signaling pathway were determined in HOPE-fixed human tumor tissues through IHC (Scoring) using tissue microarray (TMA) technique and correlated with respective uPA and PAI-1 levels determined earlier in the same TMAs through optimized IHC and semi-quantitative image analysis. TGF-β signaling was active in vast majority (96 %) of the tumor samples and 88 % of all cases were significantly correlated with established metastasis markers uPA and PAI-1. In addition, TGF-β was also closely associated with tumor size, nodal status and two steroid hormone receptors. Consistent interrelationships between TGF-β, PA components and additional tumor characteristics underline the superiority of such more comprising data with regards to confirming TGF-β signaling as a promising target system to inhibit metastasis in advanced breast cancer.

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Acknowledgments

The authors would like to thank Jasmin Tiebach, Maria Lammers and Stefanie Fox for their excellent technical support.

Conflict of Interest

There is no conflict of interest for any of the authors.

Ethics

The research protocol has been approved by the Ethics committees of Bad Segeberg (39/09) and of the University of Lübeck (07–157).

Authors’ Contributions

DSL carried out the semi-quantitative image analyses, statistical evaluation and drafted the manuscript. SM carried out and evaluated the staining’s of the TGF-β pathway members and was involved in the drafting of the manuscript. UH and OB were responsible for the surgical part and clinical data. WS and RS provided the surgical tissue material following routine pathology. MR has contributed in writing and finalizing the manuscript. EV was responsible for the histopathological aspects. TG conceived of the study and was involved in drafting the manuscript. All authors have read and approved the final manuscript.

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Authors and Affiliations

  1. Clinical and Experimental Pathology, Research Center Borstel, Parkallee 3a, 23845, Borstel, Germany

    D. S. Lang, S. Marwitz, E. Vollmer & T. Goldmann

  2. Airway Research Center North (ARCN)- Member of the German Center for Lung Research (DZL), Borstel, Germany

    D. S. Lang, S. Marwitz, M. Reck, E. Vollmer & T. Goldmann

  3. Clinical Center Itzehoe, Gynecological Hospital, Holsteinisches Breast Center, Itzehoe, Germany

    U. Heilenkötter

  4. imland Clinic Rendsburg, Pathology, Holsteinisches Breast Center, Rendsburg, Germany

    W. Schumm

  5. imland Clinic Rendsburg, Gynecological Hospital, Holsteinisches Breast Center, Rendsburg, Germany

    O. Behrens

  6. University Medical Center Hamburg Eppendorf, Pathology, Hamburg, Germany

    R. Simon

  7. LungenClinic Grosshansdorf, Oncology, Großhansdorf, Germany

    M. Reck

Authors
  1. D. S. Lang
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  2. S. Marwitz
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  3. U. Heilenkötter
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  9. T. Goldmann
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Corresponding author

Correspondence to D. S. Lang.

Additional information

D.S. Lang and S. Marwitz contributed equally to this research.

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Lang, D.S., Marwitz, S., Heilenkötter, U. et al. Transforming Growth Factor-Beta Signaling Leads to uPA/PAI-1 Activation and Metastasis: A Study on Human Breast Cancer Tissues. Pathol. Oncol. Res. 20, 727–732 (2014). https://doi.org/10.1007/s12253-014-9753-2

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  • DOI: https://doi.org/10.1007/s12253-014-9753-2

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