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T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells

Oncogene volume 29, pages 3252–3262 (2010)Cite this article

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Abstract

T-box 2 (TBX2) is a transcription factor involved in mammary development and is known to be overexpressed in a subset of aggressive breast cancers. TBX2 has previously been shown to repress growth control genes such as p14ARF and p21WAF1/cip1. In this study we show that TBX2 drives proliferation in breast cancer cells and this is abrogated after TBX2 small interfering RNA (siRNA) knockdown or after the expression of a dominant-negative TBX2 protein. Using microarray analysis we identified a large cohort of novel TBX2-repressed target genes including the breast tumour suppressor NDRG1 (N-myc downregulated gene 1). We show that TBX2 targets NDRG1 through a previously undescribed mechanism involving the recruitment of early growth response 1 (EGR1). We show EGR1 is required for the ability of TBX2 to repress NDRG1 and drive cell proliferation. We show that TBX2 interacts with EGR1 and that TBX2 requires EGR1 to target the NDRG1 proximal promoter. Abrogation of either TBX2 or EGR1 expression is accompanied by the upregulation of cell senescence and apoptotic markers. NDRG1 can recapitulate these effects when transfected into TBX2-expressing cells. Together, these data identify a novel mechanism for TBX2-driven oncogenesis and highlight the importance of NDRG1 as a growth control gene in breast tissue.

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Acknowledgements

Special thanks to Dr James Murray (CCRCB, QUB) for gift of sheep anti-human NDRG1 antibody, Professor Carlos Caldas (University of Cambridge) for TBX2-expressing breast cancer cell lines and Professor Max Costa (University of New York) for NDRG1 promoter luciferase constructs. We also thank Professor Neil Perkins (University of Bristol) for reading this manuscript. This study was supported by the Department of Employment and Learning Northern Ireland (KLR), Breast Cancer Campaign (NTC, PBM), Action Cancer (HF, PBM), OSF (ZCD’C), Cancer Research UK (GJO’B, PGJ, DPH) and Research and Development Northern Ireland (NEB).

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  1. K L Redmond and N T Crawford: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK

    K L Redmond, N T Crawford, H Farmer, Z C D'Costa, N E Buckley, P G Johnston, D P Harkin & P B Mullan

  2. Almac Diagnostics, Almac House, Craigavon, UK

    G J O'Brien, R D Kennedy & D P Harkin

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  1. K L Redmond
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  2. N T Crawford
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Correspondence to P B Mullan.

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Redmond, K., Crawford, N., Farmer, H. et al. T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells. Oncogene 29, 3252–3262 (2010). https://doi.org/10.1038/onc.2010.84

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