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

Christine Stürken, Volker Möbus, Karin Milde-Langosch, Sabine Schmatloch, Peter A Fasching, Josef Rüschoff, Elmar Stickeler, Rolf-Peter Henke, Carsten Denkert, Lars Hanker, Christian Schem, Valentina Vladimirova, Thomas Karn, Valentina Nekljudova, Claus-Henning Köhne, Frederik Marmé, Udo Schumacher, Sibylle Loibl, Volkmar Müller


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 ; registration number: NCT00196872 .

Original languageEnglish
JournalBMC Cancer
Issue number1
Pages (from-to)920
Publication statusPublished - 14.08.2021

Research Areas and Centers

  • Centers: University Cancer Center Schleswig-Holstein (UCCSH)
  • Research Area: Luebeck Integrated Oncology Network (LION)


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