We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Inhibition of interferon-signalling halts cancer-associated fibroblast-dependent protection of breast cancer cells from chemotherapy.
- Authors
Broad, Robyn V.; Jones, Stacey J.; Teske, Melina C.; Wastall, Laura M.; Hanby, Andrew M.; Thorne, James L.; Hughes, Thomas A.
- Abstract
<bold>Background: </bold>Triple negative breast cancers (TNBC) have poor prognoses despite aggressive treatment with cytotoxic chemotherapy. Cancer-associated fibroblasts (CAFs) are prominent in tumour stroma. Our hypothesis was that CAFs modulate chemotherapy sensitivity.<bold>Methods: </bold>TNBC cells and breast fibroblasts were cultured; survival after chemotherapeutics was assessed using luciferase or clonogenic assays. Signalling was investigated using transcriptomics, reporters, recombinant proteins and blocking antibodies. Clinical relevance was investigated using immunohistochemistry.<bold>Results: </bold>Breast CAFs dose-dependently protected TNBC cell lines MDA-MB-231 and MDA-MB-157, but not MDA-MB-468s, from chemotherapy. CAF-induced protection was associated with interferon (IFN) activation. CAFs were induced to express IFNβ1 by chemotherapy and TNBC co-culture, leading to paracrine activation in cancer cells. Recombinant IFNs were sufficient to protect MDA-MB-231 and MDA-MB-157 but not MDA-MB-468 cells. In TNBC patients, IFNβ1 expression in CAFs correlated with cancer cell expression of MX1, a marker of activated IFN signalling. High expression of IFNβ1 (CAFs) or MX1 (tumour cells) correlated with reduced survival after chemotherapy, especially in claudin-low tumours (which MDA-MB-231 and MDA-MB-157 cells represent). Antibodies that block IFN receptors reduced CAF-dependent chemoprotection.<bold>Conclusions: </bold>CAF-induced activation of IFN signalling in claudin-low TNBCs results in chemoresistance. Inhibition of this pathway represents a novel method to improve breast cancer outcomes.
- Subjects
PROTEIN metabolism; CANCER cell culture; PROTEINS; RESEARCH; FIBROBLASTS; RESEARCH methodology; ANTINEOPLASTIC agents; CELL physiology; APOPTOSIS; PROGNOSIS; TISSUE culture; MEDICAL cooperation; EVALUATION research; INTERFERONS; COMPARATIVE studies; GENES; GENE expression profiling; RESEARCH funding; BREAST tumors; PHARMACODYNAMICS
- Publication
British Journal of Cancer, 2021, Vol 124, Issue 6, p1110
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-020-01226-4