Details

Autor(en) / Beteiligte

• Rodriguez-Barrueco, Ruth
• Yu, Jiyang
• 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
• Silva, Jose M

Titel

Inhibition of the autocrine IL-6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers

Ist Teil von

• Genes & development, 2015-08, Vol.29 (15), p.1631-1648

Ort / Verlag

United States: Cold Spring Harbor Laboratory Press

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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.