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

doi:10.1186/s12885-021-08656-0

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

Clinic of Gynecology and Obstetrics

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 .

Original language	English
Journal	BMC Cancer
Volume	21
Issue number	1
Pages (from-to)	920
ISSN	1471-2407
DOIs	https://doi.org/10.1186/s12885-021-08656-0
Publication status	Published - 14.08.2021

Research Areas and Centers

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s12885-021-08656-0

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Stürken, C., Möbus, V., Milde-Langosch, K., Schmatloch, S., Fasching, P. A., Rüschoff, J., Stickeler, E., Henke, R-P., Denkert, C., Hanker, L., Schem, C., Vladimirova, V., Karn, T., Nekljudova, V., Köhne, C-H., Marmé, F., Schumacher, U., Loibl, S., & Müller, V. (2021). TGFB-induced factor homeobox 1 (TGIF) expression in breast cancer. BMC Cancer, 21(1), 920. https://doi.org/10.1186/s12885-021-08656-0

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title = "TGFB-induced factor homeobox 1 (TGIF) expression in breast cancer",

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 .",

author = "Christine St{\"u}rken and Volker M{\"o}bus and Karin Milde-Langosch and Sabine Schmatloch and Fasching, {Peter A} and Josef R{\"u}schoff and Elmar Stickeler and Rolf-Peter Henke and Carsten Denkert and Lars Hanker and Christian Schem and Valentina Vladimirova and Thomas Karn and Valentina Nekljudova and Claus-Henning K{\"o}hne and Frederik Marm{\'e} and Udo Schumacher and Sibylle Loibl and Volkmar M{\"u}ller",

note = "{\textcopyright} 2021. The Author(s).",

year = "2021",

month = aug,

day = "14",

doi = "10.1186/s12885-021-08656-0",

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journal = "BMC Cancer",

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Stürken, C, Möbus, V, Milde-Langosch, K, Schmatloch, S, Fasching, PA, Rüschoff, J, Stickeler, E, Henke, R-P, Denkert, C, Hanker, L, Schem, C, Vladimirova, V, Karn, T, Nekljudova, V, Köhne, C-H, Marmé, F, Schumacher, U, Loibl, S & Müller, V 2021, 'TGFB-induced factor homeobox 1 (TGIF) expression in breast cancer', BMC Cancer, vol. 21, no. 1, pp. 920. https://doi.org/10.1186/s12885-021-08656-0

TY - JOUR

T1 - TGFB-induced factor homeobox 1 (TGIF) expression in breast cancer

AU - Stürken, Christine

AU - Möbus, Volker

AU - Milde-Langosch, Karin

AU - Schmatloch, Sabine

AU - Fasching, Peter A

AU - Rüschoff, Josef

AU - Stickeler, Elmar

AU - Henke, Rolf-Peter

AU - Denkert, Carsten

AU - Hanker, Lars

AU - Schem, Christian

AU - Vladimirova, Valentina

AU - Karn, Thomas

AU - Nekljudova, Valentina

AU - Köhne, Claus-Henning

AU - Marmé, Frederik

AU - Schumacher, Udo

AU - Loibl, Sibylle

AU - Müller, Volkmar

PY - 2021/8/14

Y1 - 2021/8/14

N2 - 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 .

AB - 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 .

U2 - 10.1186/s12885-021-08656-0

DO - 10.1186/s12885-021-08656-0

M3 - Journal articles

C2 - 34391399

SN - 1471-2407

VL - 21

SP - 920

JO - BMC Cancer

JF - BMC Cancer

IS - 1

ER -

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

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