Paracrine IL-6 Signaling Confers Proliferation between Heterogeneous Inflammatory Breast Cancer Sub-Clones

SIMPLE SUMMARY: This study provides novel mechanistic insights into the capacity of the inflammatory cytokine IL-6 and its associated STAT3-dependent signaling pathway to stimulate proliferation in trans between individual sub-clones in a model of heterogeneity in inflammatory breast cancer. The clinical relevance of this discovery is provided by our observation that proliferation of the IL-6 responsive subclone is sensitive to inhibition with the clinically approved anti-IL-6 receptor humanized monoclonal antibody Tocilizumab. These findings therefore provide a rationale for potentially repurposing Tocilizumab for the treatment of a subset of inflammatory breast cancer patients. ABSTRACT: Inflammatory breast cancer (IBC) describes a highly aggressive form of breast cancer of diverse molecular subtypes and clonal heterogeneity across individual tumors. Accordingly, IBC is recognized by its clinical signs of inflammation, associated with expression of interleukin (IL)-6 and other inflammatory cytokines. Here, we investigate whether sub-clonal differences between expression of components of the IL-6 signaling cascade reveal a novel role for IL-6 to mediate a proliferative response in trans using two prototypical IBC cell lines. We find that SUM149 and SUM 190 cells faithfully replicate differential expression observed in a subset of human IBC specimens between IL-6, the activated form of the key downstream transcription factor STAT3, and of the HER2 receptor. Surprisingly, the high level of IL-6 produced by SUM149 cells activates STAT3 and stimulates proliferation in SUM190 cells, but not in SUM149 cells with low IL-6R expression. Importantly, SUM149 conditioned medium or co-culture with SUM149 cells induced growth of SUM190 cells, and this effect was abrogated by the IL-6R neutralizing antibody Tocilizumab. The results suggest a novel function for inter-clonal IL-6 signaling in IBC, whereby IL-6 promotes in trans proliferation of IL-6R and HER2-expressing responsive sub-clones and, therefore, may provide a vulnerability that can be exploited therapeutically by repurposing of a clinically approved antibody.