TGFB-induced factor homeobox 1 (TGIF) expression in breast cancer

BMC Cancer, vol. 21, pp. 920

Abstract

BACKGROUND: Breast cancer (BC) is the most frequent female cancer and preferentially metastasizes to bone. The transcription factor TGFB-induced factor homeobox 1 (TGIF) is involved in bone metabolism. However, it is not yet known whether TGIF is associated with BC bone metastasis or patient outcome and thus of potential interest. METHODS: TGIF expression was analyzed by immunohistochemistry in 1197 formalin-fixed, paraffin-embedded tissue samples from BC patients treated in the GAIN (German Adjuvant Intergroup Node-Positive) study with two adjuvant dose-dense schedules of chemotherapy with or without bisphosphonate ibandronate. TGIF expression was categorized into negative/low and moderate/strong staining. Endpoints were disease-free survival (DFS), overall survival (OS) and time to primary bone metastasis as first site of relapse (TTPBM). RESULTS: We found associations of higher TGIF protein expression with smaller tumor size (p = 0.015), well differentiated phenotype (p < 0.001) and estrogen receptor (ER)-positive BC (p < 0.001). Patients with higher TGIF expression levels showed a significantly longer disease-free (DFS: HR 0.75 [95%CI 0.59-0.95], log-rank p = 0.019) and overall survival (OS: HR 0.69 [95%CI 0.50-0.94], log-rank p = 0.019), but no association with TTPBM (HR 0.77 [95%CI 0.51-1.16]; p = 0.213). Univariate analysis in molecular subgroups emphasized that elevated TGIF expression was prognostic for both DFS and OS in ER-positive BC patients (DFS: HR 0.68 [95%CI 0.51-0.91]; log-rank p = 0.009, interaction p = 0.130; OS: HR 0.60 [95%CI 0.41-0.88], log-rank p = 0.008, interaction p = 0.107) and in the HER2-negative subgroup (DFS:HR 0.67 [95%CI 0.50-0.88], log-rank p = 0.004, interaction p = 0.034; OS: HR 0.57 [95%CI 0.40-0.81], log-rank p = 0.002, interaction p = 0.015). CONCLUSIONS: Our results suggest that moderate to high TGIF expression is a common feature of breast cancer cells and that this is not associated with bone metastases as first site of relapse. However, a reduced expression is linked to tumor progression, especially in HER2-negative breast cancer. TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov ; registration number: NCT00196872 .

Authors 19

1. Christine Stürken

   University Medical Center Hamburg-Eppendorf

   Affiliation as printed

   Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

2. Volker J. Möbus

   Klinikum Frankfurt Höchst

   Affiliation as printed

   Klinik für Gynäkologie und Geburtshilfe, Klinikum Frankfurt Höchst GmbH, Frankfurt am Main, Germany

3. Karin Milde‐Langosch

   University Medical Center Hamburg-Eppendorf

   Affiliation as printed

   Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

4. Sabine Schmatloch
   Affiliation as printed

   Elisabeth Krankenhaus Kassel, Kassel, Germany

5. Peter Andreas Fasching

   Universitätsklinikum Erlangen

   Affiliation as printed

   Universitätsklinikum Erlangen, Erlangen, Germany

6. Josef Rüschoff
   Affiliation as printed

   Elisabeth Krankenhaus Kassel, Kassel, Germany

7. Elmar Stickeler Aachen

   Universitätsklinikum Aachen

   Affiliation as printed

   Uniklinik RWTH Aachen, Aachen, Germany

8. Rolf‐Peter Henke

   Klinikum Oldenburg

   Affiliation as printed

   Klinikum Oldenburg, Oldenburg, Germany

9. Carsten Denkert

   Philipps University of Marburg · Universitätsklinikum Gießen und Marburg

   Affiliation as printed

   Institute of Pathology, Philipps-University Marburg and University Hospital Marburg (UKGM), Marburg, Germany

10. Lars Hanker

    University Hospital Schleswig-Holstein · Goethe University Frankfurt

    Affiliation as printed

    Department of Gynecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Lübeck, Kiel, Germany

    Goethe University, Frankfurt, Germany

11. Christian Schem

    Mammazentrum Hamburg

    Affiliation as printed

    Mammazentrum Hamburg, Hamburg, Germany

12. Valentina A. Vladimirova

    German Breast Group

    Affiliation as printed

    German Breast Group, Neu-Isenburg, Germany

13. Thomas Karn

    Goethe University Frankfurt

    Affiliation as printed

    Goethe University, Frankfurt, Germany

14. Valentina Nekljudova

    German Breast Group

    Affiliation as printed

    German Breast Group, Neu-Isenburg, Germany

15. Claus‐Henning Köhne

    Klinikum Oldenburg

    Affiliation as printed

    Klinikum Oldenburg, Oldenburg, Germany

16. Frederik Marmé

    Heidelberg University · Medizinische Fakultät Mannheim

    Affiliation as printed

    Medizinische Fakultät Mannheim, Universität Heidelberg, Universitätsfrauenklinik Mannheim, Mannheim, Germany

17. Udo Schumacher

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

18. Sibylle Loibl

    German Breast Group

    Affiliation as printed

    German Breast Group, Neu-Isenburg, Germany

19. Volkmar Müller corresponding

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. vmueller@uke.de

    Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany