Article (Scientific journals)
Systematic functional perturbations uncover a prognostic genetic network driving human breast cancer
Gallenne, Tristan; Ross, Kenneth N.; Visser, Nils L. et al.
2017In Oncotarget, 8 (13), p. 20572-20587
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Keywords :
breast cancer; metastasis; prognosis; tumor biology
Abstract :
[en] Prognostic classifiers conceivably comprise biomarker genes that functionally contribute to the oncogenic and metastatic properties of cancer, but this has not been investigated systematically. The transcription factor Fra-1 not only has an essential role in breast cancer, but also drives the expression of a highly prognostic gene set. Here, we systematically perturbed the function of 31 individual Fra-1-dependent poor-prognosis genes and examined their impact on breast cancer growth in vivo. We find that stable shRNA depletion of each of nine individual signature genes strongly inhibits breast cancer growth and aggressiveness. Several factors within this ninegene set regulate each other’s expression, suggesting that together they form a network. The ninegene set is regulated by estrogen, ERBB2 and EGF signaling, all established breast cancer factors. We also uncover three transcription factors, MYC, E2F1 and TP53, which act alongside Fra-1 at the core of this network. ChIP-Seq analysis reveals that a substantial number of genes are bound, and regulated, by all four transcription factors. The nine-gene set retains significant prognostic power and includes several potential therapeutic targets, including the bifunctional enzyme PAICS, which catalyzes purine biosynthesis. Depletion of PAICS largely cancelled breast cancer expansion, exemplifying a prognostic gene with breast cancer activity. Our data uncover a core genetic and prognostic network driving human breast cancer. We propose that pharmacological inhibition of components within this network, such as PAICS, may be used in conjunction with the Fra-1 prognostic classifier towards personalized management of poor prognosis breast cancer.
Disciplines :
Oncology
Author, co-author :
Gallenne, Tristan ;  The Netherlands Cancer Institute, Plesmanlaan, CX, Amsterdam, The Netherlands > Department of Molecular Oncology
Ross, Kenneth N. ;  Massachusetts General Hospital Cancer Center, Boston, MA, USA
Visser, Nils L. ;  The Netherlands Cancer Institute, Plesmanlaan, CX, Amsterdam, The Netherlands > Department of Molecular Oncology
Salony, - ;  Massachusetts General Hospital Cancer Center, Boston, MA, USA
Desmet, Christophe  ;  ULiège, Département des sciences fonctionnelles (DSF), GIGA-R : Biochimie et biologie moléculaire > Department of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan, CX, Amsterdam, The Netherlands
Wittner, Ben S.;  Massachusetts General Hospital Cancer Center, Boston, MA, USA
Wessels, Lodewyk F.A.;  The Netherlands Cancer Institute, Plesmanlaan, CX, Amsterdam, The Netherlands > Department of Molecular Carcinogenesis
Ramaswamy, Sridhar;  Massachusetts General Hospital Cancer Center, Boston, MA, USA
Peeper, Daniel Simon;  The Netherlands Cancer Institute, Plesmanlaan, CX, Amsterdam, The Netherlands > Department of Molecular Oncology
 These authors have contributed equally to this work.
Language :
English
Title :
Systematic functional perturbations uncover a prognostic genetic network driving human breast cancer
Publication date :
2017
Journal title :
Oncotarget
eISSN :
1949-2553
Publisher :
Impact Journals, United States - New York
Volume :
8
Issue :
13
Pages :
20572-20587
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 12 December 2018

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