1. Inhibition of the autocrine IL-6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers.
- Author
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Rodriguez-Barrueco, Ruth, Jiyang Yu, Saucedo-Cuevas, Laura P., Olivan, Mireia, Llobet-Navas, David, Putcha, Preeti, Castro, Veronica, Murga-Penas, Eva M., Collazo-Lorduy, Ana, Castillo-Martin, Mireia, Alvarez, Mariano, Cordon-Cardo, Carlos, Kalinsky, Kevin, Maurer, Matthew, Califano, Andrea, and Silva, Jose M.
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GENETIC testing , *HER2 gene , *ADENOCARCINOMA , *BREAST cancer research , *HORMONE receptors - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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