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

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.

Interaction between Macrophages and Adipose Stromal Cells Increases the Angiogenic and Proliferative Potential of Pregnancy-Associated Breast Cancers

“…MIP-1alpha increased in the co-culture media when compared to ASC-L media alone, and MMP-3 increased in the co-culture media when compared to macrophage media alone. These are all cytokines that have been shown to increase tumor aggression [ 18 , 19 , 20 , 21 , 22 , 23 , 24 ].…”

Crosstalk of Inflammatory Cytokines within the Breast Tumor Microenvironment

“…Therefore, blocking IL-6 (i.e., anti-IL-6 therapy), targeting its receptor in combination with signaling from other anticancer therapies, and targeting the IL-6-STAT3 axis is a potential therapeutic strategy that may be beneficial in the treatment of breast cancer [ 206 , 288 , 289 ]. Down-regulation of IL-6 is linked to a better response to breast cancer treatment [ 290 ] and a recent study showed that the IL-6R neutralizing antibody, tocilizumab, abrogated IL-6 signaling in breast cancer [ 291 ]. A synthetic anti-gp130 compound (bazedoxifene) inhibited IL-6-induced growth of breast cancer cell lines and down-regulated STAT3 phosphorylation [ 292 ].…”

IL-6: The Link Between Inflammation, Immunity and Breast Cancer

“…The signature of IBC is recognized by its inflammation feature which is associated with IL-6 expression. A recent study published in May 2022 revealed that IL-6 signaling stimulate cell proliferation in IL-6R and HER2-expressing responsive sub-clones in IBC, and this effect was abrogated by the IL-6R neutralizing antibody Tocilizumab ( 103 ).…”