Rodriguez-Barrueco, RuthYu, JiyangSaucedo-Cuevas, Laura P.Olivan Riera, MireiaLlobet-Navas, DavidPutcha, PreetiCastro, VerónicaMurga-Penas, Eva M.Collazo-Lorduy, AnaCastillo Martin, MireiaÁlvarez, MarianoCordon Cardo, CarlosKalinsky, KevinMaurer, MatthewCalifano, AndreaSilva, José2020-07-142020-07-142015-08-010890-9369https://hdl.handle.net/2445/168553HER2-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.18 p.application/pdfeng(c) Rodriguez-Barrueco, Ruth et al., 2015Càncer de mamaExpressió gènicaFactors de transcripcióBreast cancerGene expressionTranscription factorsinfo:eu-repo/semantics/article6949592020-07-14info:eu-repo/semantics/openAccess26227964