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http://hdl.handle.net/2445/168553
Title: | Inhibition of the autocrine IL-6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers |
Author: | Rodriguez-Barrueco, Ruth Yu, Jiyang Saucedo-Cuevas, Laura P. Olivan Riera, Mireia Llobet-Navas, David Putcha, Preeti Castro, Verónica Murga-Penas, Eva M. Collazo-Lorduy, Ana Castillo Martin, Mireia Álvarez, Mariano Cordon Cardo, Carlos Kalinsky, Kevin Maurer, Matthew Califano, Andrea Silva, José |
Keywords: | Càncer de mama Expressió gènica Factors de transcripció Breast cancer Gene expression Transcription factors |
Issue Date: | 1-Aug-2015 |
Publisher: | Cold Spring Harbor Laboratory Press |
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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1101/gad.262642.115 |
It is part of: | Genes & Development, 2015, vol. 29, num. 15, p. 1631-1648 |
URI: | http://hdl.handle.net/2445/168553 |
Related resource: | https://doi.org/10.1101/gad.262642.115 |
ISSN: | 0890-9369 |
Appears in Collections: | Articles publicats en revistes (Patologia i Terapèutica Experimental) |
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