In:
Genes & Development, Cold Spring Harbor Laboratory, Vol. 29, No. 15 ( 2015-08-01), p. 1631-1648
Abstract:
HER2-positive (HER2 + ) breast adenocarcinomas are a heterogeneous group in which hormone receptor (HR) status influences therapeutic decisions and patient outcome. By combining genome-wide RNAi screens with regulatory network analysis, we identified STAT3 as a critically activated master regulator of HR − /HER2 + tumors, eliciting tumor dependency in these cells. Mechanistically, HR − /HER2 + cells secrete high levels of the interleukin-6 (IL-6) cytokine, inducing the activation of STAT3, which in turn promotes a second autocrine stimulus to increase S100A8/9 complex (calprotectin) production and secretion. Increased calprotectin levels activate signaling pathways involved in proliferation and resistance. Importantly, we demonstrated that inhibition of the IL-6–Janus kinase 2 (JAK2)–STAT3–calprotectin axis with FDA-approved drugs, alone and in combination with HER2 inhibitors, reduced the tumorigenicity of HR − /HER2 + breast cancers, opening novel targeted therapeutic opportunities.
Type of Medium:
Online Resource
ISSN:
0890-9369
,
1549-5477
DOI:
10.1101/gad.262642.115
Language:
English
Publisher:
Cold Spring Harbor Laboratory
Publication Date:
2015
detail.hit.zdb_id:
1467414-2
SSG:
12
Bookmarklink
