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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:
It is part of: Genes & Development, 2015, vol. 29, num. 15, p. 1631-1648
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ISSN: 0890-9369
Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)

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