Rcl is a novel ETV1/ER81 target gene upregulated in breast tumors

Sook Shin, Denis G. Bosc, James N. Ingle, Thomas C. Spelsberg, Ralf Janknecht

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

ETV1 (ER81) is a transcription factor that can be activated by HER2/Neu, a proto-oncoprotein often overexpressed in metastatic breast tumors. Here, we demonstrate that ETV1 downregulation suppresses proliferation of HER2/Neu-positive MDA-MB-231 breast cancer cells in vitro and tumor formation in vivo, proving for the first time the existence of a critical role of ETV1 in breast cancer cell physiology. A screen for novel ETV1 target genes hinted at Rcl, an enzyme involved in nucleotide metabolism. To characterize the human Rcl gene, we cloned its promoter and found that ETV1 and HER2/Neu cooperated in activating the Rcl promoter, whereas a dominant-negative ETV1 molecule suppressed the Rcl promoter. Moreover, ETV1 and HER2/Neu synergized to upregulate the endogenous Rcl gene. ETV1 also bound to the Rcl promoter in vivo, indicating that Rcl is a bona fide target gene of ETV1. Hybridization of Rcl cDNA to a breast cancer array revealed that Rcl is overexpressed in ∼40% of all breast tumors. Importantly, its expression significantly escalates with increasing tumor grade, strongly implicating that Rcl contributes to breast tumorigenesis. Since joint overexpression of Rcl with vascular endothelial growth factor, another target gene of ETV1, has been shown to induce tumor formation, Rcl may be one crucial effector of ETV1 and HER2/Neu in breast tumors. Furthermore, given its expression pattern and enzymatic function in nucleotide metabolism, Rcl presents itself as a novel target in breast cancer therapy via modulation of its activity by small molecule drugs.

Original languageEnglish (US)
Pages (from-to)866-874
Number of pages9
JournalJournal of cellular biochemistry
Volume105
Issue number3
DOIs
StatePublished - Oct 15 2008

Keywords

  • Breast cancer
  • ER81
  • ETV1
  • HER2/NEU
  • RCL

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Shin, S., Bosc, D. G., Ingle, J. N., Spelsberg, T. C., & Janknecht, R. (2008). Rcl is a novel ETV1/ER81 target gene upregulated in breast tumors. Journal of cellular biochemistry, 105(3), 866-874. https://doi.org/10.1002/jcb.21884