Editors' ChoiceCancer

Cytokine loops promote breast cancer

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Sci. Signal.  25 Aug 2015:
Vol. 8, Issue 391, pp. ec235
DOI: 10.1126/scisignal.aad2807

The growth of some breast cancers is mediated by increased activity of the epidermal growth factor receptor HER2, but targeting HER2 directly has not been effective in halting tumor growth and progression. Rodriguez-Barrueco et al. found that the growth of HER2-positive tumors is driven by autocrine cytokine signaling that is targetable with FDA-approved drugs. Bioinformatics analysis combined with genome-wide RNA-interference screens in cultured cells and in orthotopic xenografts in mice revealed that the transcription factor STAT3 was a critical promoter of proliferation in MCF10A cells that were transformed with an oncogenic form of HER2 (MCF10AHER2*). Compared with controls, MCF10AHER2* cells had increased STAT3 abundance and activity as detected by a cotransfected STAT3-target luciferase reporter. STAT3 activation in MCF10AHER2* cells was decreased when the kinase JAK2 was inhibited. The gene encoding the cytokine IL-6, which activates STAT3, showed the greatest increase in expression in MCF10AHER2* cells. Incubating control cells with conditioned medium from MCF10AHER2* cells induced STAT3 phosphorylation, an effect that was prevented by an IL-6 receptor blocking antibody. Silencing STAT3 decreased the expression of the genes encoding S100A and S100B, small cytoplasmic calcium-binding proteins that heterodimerize to form the secreted complex calprotectin, whereas IL-6 exposure increased the expression of these genes. Silencing STAT3 decreased the proliferation of MCF10AHER2* cells in vitro and in vivo but not that of MCF10A or MDA-MB-231 cells bearing wild-type HER2. Ectopic expression of S100A and S100B restored proliferation in STAT3-deficient MCF10AHER2* cells and increased the phosphorylation of AKT, a kinase that is stimulated by HER2 to promote cell proliferation. Treating MCF10AHER2* cells with the S1009 inhibitor tasquinimod suppressed AKT phosphorylation despite the presence of oncogenic HER2. The phosphorylation of STAT3 correlated with the expression of IL-6, S100A, and S100B in breast cancer patient samples, and the expression of these strongly correlated with HER2 positivity. Treating HER2-positive cell line–derived or patient-derived xenografts with a combination of the FDA-approved JAK inhibitor ruxolitinib and the HER2-blocking antibody trastuzumab suppressed tumor growth. The findings suggest that targeting JAK-STAT signaling–mediated cytokine production may improve therapeutic outcomes in HER2-positive breast cancer patients.

R. Rodriguez-Barrueco, J. Yu, L. P. Saucedo-Cuevas, M. Olivan, D. Llobet-Navas, P. Putcha, V. Castro, E. M. Murga-Penas, A. Collazo-Lorduy, M. Castillo-Martin, M. Alvarez, C. Cordon-Cardo, K. Kalinsky, M. Maurer, A. Califano, J. M. Silva, Inhibition of the autocrine IL-6–JAK2–STAT3–calprotectin axis as targeted therapy for HR/HER2+ breast cancers. Genes Dev. 29, 1631–1648 (2015). [PubMed]