ABSTRACT
Tissue inhibitor of metalloprotease 4 (TIMP4) contributes to poor prognosis in breast and other tumours. However, the mechanisms of how TIMP4 influences breast cancer cell behaviour are unknown. Our aim was to explore the signalling pathways modulated by TIMP4 in breast cancer cells. Human recombinant TIMP4 was added to MCF7 breast cancer cells and RNASeq was performed. TIMP4 RNASeq results were validated by RT-PCR. Network analyses of TIMP4-exposed cells showed that ER-α, HIF1A and TGF-ß signalling were activated, whereas FOXO3 signalling was downregulated. ER-α protein levels were increased and concordantly, promoters of TIMP4-upregulated genes were significantly enriched in oestrogen-binding sites. We concluded that TIMP4 modulates multiple signalling pathways relevant in cancer in MCF7 cells, including the ER-α cascade.
Subject(s)
Estrogen Receptor alpha/metabolism , Signal Transduction , Tissue Inhibitor of Metalloproteinases/metabolism , Blotting, Western , Breast Neoplasms/physiopathology , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Humans , MCF-7 Cells , Real-Time Polymerase Chain Reaction , Recombinant Proteins/pharmacology , Signal Transduction/drug effects , Tissue Inhibitor of Metalloproteinases/genetics , Tissue Inhibitor of Metalloproteinases/pharmacology , Tissue Inhibitor of Metalloproteinase-4ABSTRACT
BACKGROUND: Cancer stem cells (CSCs) are regulated by several signaling pathways that ultimately control their maintenance and expansion. NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) forms a protein complex that controls DNA transcription and, as such, plays an important role in proliferation, inflammation, angiogenesis, invasion and metastasis. The NF-κB signaling pathway, which has been found to be constitutively activated in CSCs from a variety of cancers, participates in the maintenance, expansion, proliferation and survival of CSCs. Targeted disruption of this pathway may profoundly impair the adverse phenotype of CSCs and may provide a therapeutic opportunity to remove the CSC fraction. In particular, it may be attractive to use specific NF-κB inhibitors in chronic therapeutic schemes to reduce disease progression. Exceptional low toxicity profiles of these inhibitors are a prerequisite for use in combined treatment regimens and to avoid resistance. CONCLUSION: Although still preliminary, recent evidence shows that such targeted strategies may be useful in adjuvant chemo-preventive settings.