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Lookup NU author(s): Dr Ruth Rodriguez Barrueco, Dr David Llobet-Navas
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
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.
Author(s): Rodriguez-Barrueco R, Yu J, Saucedo-Cuevas LP, Olivan M, Llobet-Navas D, Putcha P, Castro V, Murga-Penas EM, Collazo-Lorduy A, Castillo-Martin M, Alvarez M, Cordon-Cardo C, Kalinsky K, Maurer M, Califano A, Silva JM
Publication type: Article
Publication status: Published
Journal: Genes & Development
Year: 2015
Volume: 29
Issue: 15
Pages: 1631-1648
Print publication date: 01/08/2015
Online publication date: 30/07/2015
Acceptance date: 14/07/2015
Date deposited: 02/09/2016
ISSN (print): 0890-9369
ISSN (electronic): 1549-5477
Publisher: CSH Press
URL: http://dx.doi.org/10.1101/gad.262642.115
DOI: 10.1101/gad.262642.115
PubMed id: 26227964
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