TY - JOUR
T1 - Rcl is a novel ETV1/ER81 target gene upregulated in breast tumors
AU - Shin, Sook
AU - Bosc, Denis G.
AU - Ingle, James N.
AU - Spelsberg, Thomas C.
AU - Janknecht, Ralf
PY - 2008/10/15
Y1 - 2008/10/15
N2 - 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.
AB - 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.
KW - Breast cancer
KW - ER81
KW - ETV1
KW - HER2/NEU
KW - RCL
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U2 - 10.1002/jcb.21884
DO - 10.1002/jcb.21884
M3 - Article
C2 - 18726892
AN - SCOPUS:54849420699
SN - 0730-2312
VL - 105
SP - 866
EP - 874
JO - Journal of cellular biochemistry
JF - Journal of cellular biochemistry
IS - 3
ER -