Austin Health

Title
Paracrine IL-6 Signaling Confers Proliferation between Heterogeneous Inflammatory Breast Cancer Sub-Clones.
Publication Date
2022-05-04
Author(s)
Morrow, Riley J
Allam, Amr H
Yeo, Belinda
Deb, Siddhartha
Murone, Carmel
Lim, Elgene
Johnstone, Cameron N
Ernst, Matthias
Subject
HER2
Tocilizumab
heterogeneity
inflammatory breast cancer
interleukin-6
pSTAT3
paracrine
Type of document
Journal Article
OrcId
0000-0003-2283-3970
0000-0001-8065-8838
0000-0002-6464-8661
0000-0002-6399-1177
0000-0002-8743-3639
0000-0002-9218-9917
DOI
10.3390/cancers14092292
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.
Link
Citation
Cancers 2022-05-04; 14(9): 2292.
Jornal Title
Cancers
ISSN
2072-6694

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