Network analysis reveals Cnot2 and miR-3470 transcriptional circuitry regulates breast cancer metastasis in vivo

Friday, November 08, 2013 — Poster Session IV
2:00 p.m. – 4:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NCI	STRUCTBIO-4

* FARE Award Winner

Authors

F Faraji
Y Hu
G Wu
K Buetow
J Zhang
KW Hunter

Abstract

Prognostic gene signatures to predict patient risk for metastatic disease are in clinical trials; however, these gene sets provide little insight into mechanisms of metastasis. Here we exploit the notion that metastatic propensity is modified by the genetic background to link prognostic gene signatures with molecular mechanisms driving metastasis. We employ gene expression profiling of tumors of the AKXD recombinant inbred panel followed by network analysis to identify a network of co-expressed genes centered on Cnot2 that predicts metastasis free survival in breast cancer patients. Modulating Cnot2 expression impacts tumor cell metastatic potential in vivo. miR-seq analysis in the same tumor panel revealed miRNA-3470b as a potential upstream regulator of the Cnot2 network. As such, overexpression of miR-3470b down-regulated expression of network hub genes and enhanced metastasis, phenocopying Cnot2 knock-down. We further demonstrate that Cnot2 physically interacts with the pro-metastatic short isoform of Brd4, but not the anti-metastatic long isoform of Brd4 and show that Cnot2 binds the metastasis driver genes Rrp1b and Sipa1, further supporting its causal in metastasis. Here we identify a gene expression signature regulated by miR-3470b whose central node, Cnot2, functionally regulates metastasis and connect miR-3470b and Cnot2 to metastasis modifier genes involved in chromatin regulation.