TY - JOUR
T1 - Systematic functional perturbations uncover a prognostic genetic network driving human breast cancer
AU - Gallenne, Tristan
AU - Ross, Kenneth N.
AU - Visser, Nils L.
AU - Salony, null
AU - Desmet, Christian J.
AU - Wittner, Ben S.
AU - Wessels, Lodewyk
AU - Ramaswamy, Sridhar
AU - Peeper, Daniel Ss
PY - 2017
Y1 - 2017
N2 - 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 nine-gene 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.
AB - 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 nine-gene 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.
KW - Breast cancer
KW - Metastasis
KW - Prognosis
KW - Tumor biology
UR - http://www.scopus.com/inward/record.url?scp=85016398097&partnerID=8YFLogxK
UR - http://resolver.tudelft.nl/uuid:8e8d0cc5-4e45-49c7-b884-872bc30608e9
U2 - 10.18632/oncotarget.16244
DO - 10.18632/oncotarget.16244
M3 - Article
C2 - 28411283
SN - 1949-2553
VL - 8
SP - 20572
EP - 20587
JO - OncoTarget
JF - OncoTarget
IS - 13
ER -