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 nine-gene 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.