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.
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.
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.
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.
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Fiona Errington-Mais and Andrew Macdonald (both University of Leeds, UK) kindly provided materials for the study.
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Ethical permissions for use of patient material and data from patients was granted by Leeds (East) REC (references 09/H1326/108 and 06/Q1206/180). Patients recruited and informed consent was taken in line with these permissions. The study was performed in accordance with the Declaration of Helsinki.
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The authors declare no competing interests.
R.V.B. was supported by Breast Cancer Action (charity #1170369-9) and a studentship from the University of Leeds. J.L.T. was supported by a University Academic Fellowship from the University of Leeds. L.M.W. was supported by a fellowship from the Leeds CRUK Cancer Centre.
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Broad, R.V., Jones, S.J., Teske, M.C. et al. Inhibition of interferon-signalling halts cancer-associated fibroblast-dependent protection of breast cancer cells from chemotherapy. Br J Cancer (2021). https://doi.org/10.1038/s41416-020-01226-4