title: Inhibition of the autocrine IL-6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers.
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.
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
authors.forename: Ruth
authors.initials: R
authors.lastname: Rodriguez-Barrueco
authors.affiliation: Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA;
authors.forename: Jiyang
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
authors.forename: Laura P
authors.initials: LP
authors.lastname: Saucedo-Cuevas
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
authors.forename: Mireia
authors.initials: M
authors.lastname: Olivan
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
authors.forename: David
authors.initials: D
authors.lastname: Llobet-Navas
authors.affiliation: Institute for Cancer Genetics, Department of Pathology, Irving Cancer Research Center, Columbia University, New York, New York 10032, USA;
authors.forename: Preeti
authors.initials: P
authors.lastname: Putcha
authors.affiliation: Institute for Cancer Genetics, Department of Pathology, Irving Cancer Research Center, Columbia University, New York, New York 10032, USA;
authors.forename: Veronica
authors.initials: V
authors.lastname: Castro
authors.affiliation: Institute for Cancer Genetics, Department of Pathology, Irving Cancer Research Center, Columbia University, New York, New York 10032, USA;
authors.forename: Eva M
authors.initials: EM
authors.lastname: Murga-Penas
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
authors.forename: Ana
authors.initials: A
authors.lastname: Collazo-Lorduy
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo-Martin
authors.affiliation: Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA;
authors.forename: Mariano
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA;
authors.forename: Kevin
authors.initials: K
authors.lastname: Kalinsky
authors.affiliation: Institute for Cancer Genetics, Department of Pathology, Irving Cancer Research Center, Columbia University, New York, New York 10032, USA; Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA;
authors.forename: Matthew
authors.initials: M
authors.lastname: Maurer
authors.affiliation: Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA; Department of Biomedical Informatics, Institute for Cancer Genetics, Columbia University, New York, New York 10032; Department of Biochemistry and Molecular Biophysics, Institute for Cancer Genetics, Columbia University, New York, New York 10032.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
authors.forename: Jose M
authors.initials: JM
authors.lastname: Silva
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D064593:Heterografts; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D011804:Quinolines / Q000494:pharmacology; D015363:Quinolones; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015850:Interleukin-6; D011804:Quinolines; D015363:Quinolones; D050796:STAT3 Transcription Factor; C516109:tasquinimod; D053614:Janus Kinase 2; C502936:tocilizumab
keywords: HER2; STAT3; breast cancer; genetic screen; tailored therapies