Inhibition of RAC1 activity in cancer associated fibroblasts favours breast tumour development through IL-1β upregulation

Cancer-associated fibroblasts (CAFs) are highly abundant stromal components in the tumour microenvironment. These cells contribute to tumorigenesis and indeed, they have been proposed as a target for anti-cancer therapies. Similarly, targeting the Rho-GTPase RAC1 has also been suggested as a potenti...

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Bibliographic Details
Published in:Cancer letters 2021-11, Vol.521, p.14-28
Main Authors: Martínez-López, Angélica, García-Casas, Ana, Bragado, Paloma, Orimo, Akira, Castañeda-Saucedo, Eduardo, Castillo-Lluva, Sonia
Format: Article
Language:English
Subjects:
Angiogenesis
Antibodies
Biotechnology
Breast cancer
Cancer-associated fibroblasts
Cell adhesion & migration
Experiments
Fibroblasts
Genotype & phenotype
Glycerol
Growth factors
Guanine nucleotide-binding protein
IL-1β
Medical prognosis
Metastasis
Microenvironments
Phenotypes
Proteins
Rac1 protein
Stromal RAC1
Tumor microenvironment
Tumorigenesis
Tumors
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Summary:Cancer-associated fibroblasts (CAFs) are highly abundant stromal components in the tumour microenvironment. These cells contribute to tumorigenesis and indeed, they have been proposed as a target for anti-cancer therapies. Similarly, targeting the Rho-GTPase RAC1 has also been suggested as a potential therapeutic target in cancer. Here, we show that targeting RAC1 activity, either pharmacologically or by genetic silencing, increases the pro-tumorigenic activity of CAFs by upregulating IL-1β secretion. Moreover, inhibiting RAC1 activity shifts the CAF subtype to a more aggressive phenotype. Thus, as RAC1 suppresses the secretion of IL-1β by CAFs, reducing RAC1 activity in combination with the depletion of this cytokine should be considered as an interesting therapeutic option for breast cancer in which tumour cells retain intact IL-1β signalling. •Inhibition of RAC1 activity promotes the pro-tumorigenic activity of Cancer-Associated Fibroblasts (CAFs).•RAC1 inhibition enhances IL-1β secretion by breast cancer CAFs.•RAC1 inhibition is potentially a more effective therapeutic target in breast cancer when IL-1β signalling is defective.•Inhibition of RAC1 activity drives changes in the CAF subtype in breast cancer.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2021.08.014