GTSE1: a novel TEAD4-E2F1 target gene involved in cell protrusions formation in triple-negative breast cancer cell models.

Debora Stelitano,Claudio Schneider,Yamila Peche Leticia,Emiliano Dalla,Silvano Piazza,Martin Monte

doi:10.18632/oncotarget.18691

Abstract

GTSE1 over-expression has been reported as a potential marker for metastasis in various types of malignancies, including breast cancer. Despite this, the transcriptional regulation of this protein and the causes of its misregulation in tumors remain largely unknown. The aims of this work were to elucidate how GTSE1 is regulated at the transcriptional level and to clarify the mechanism underlying GTSE1-dependent cell functions in triple-negative breast cancer (TNBC).Here, we identified GTSE1 as a novel target gene of the TEAD4 transcription factor, highlighting a role for the YAP and TAZ coactivators in the transcriptional regulation of GTSE1.Moreover, we found that TEAD4 controls the formation of cell protrusions required for cell migration through GTSE1, unveiling a relevant effector role for this protein in the TEAD-dependent cellular functions and confirming TEAD4 role in promoting invasion and metastasis in breast cancer.Finally, we highlighted a role for the pRb-E2F1 pathway in the control of GTSE1 transcription and observed that treatment with drugs targeting the pRb-E2F1 or YAP/TAZ-TEAD pathways dramatically downregulated the expression levels of GTSE1 and of other genes involved in the formation of metastasis, suggesting their potential use in the treatment of TNBC.

Highlights

Breast cancer is one of the most frequently diagnosed forms of cancer and the second leading cause of death in Western women [1]
In order to obtain the best candidates to the role of regulators of GTSE1 transcription, we overlapped these results with the output generated by the TRANSFAC/Match tool [29], listing the transcription factors (TFs) exhibiting at least one binding site (TFBS) in the genomic region corresponding to the GTSE1 promoter
We evaluated the effect of TEAD1/3/4 knockdown on GTSE1 expression levels using a siRNA to silence TEAD1/3/4 in the MDA-MB-231 cell line and assessing GTSE1 protein levels after 72 hours

Summary

Introduction

Breast cancer is one of the most frequently diagnosed forms of cancer and the second leading cause of death in Western women [1]. It is a genetically and clinically heterogeneous disease [2], so no standard therapy is available for all the possible subtypes. About 15% of all invasive breast tumours are triple-negative breast cancers (TNBC) [3]. We reported that GTSE1 (G2 and S phase expressed 1) expression was up-regulated in breast cancer, especially in TNBC [4]. In transformed cells GTSE1 protein levels are elevated across all the cell cycle phases [4]

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Conclusion