TIMP4 Modulates ER-α Signalling in MCF7 Breast Cancer Cells.

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-β 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.

[1]  Andreas Krämer,et al.  Causal analysis approaches in Ingenuity Pathway Analysis , 2013, Bioinform..

[2]  Limin Liu,et al.  Estrogen-Induced Nongenomic Calcium Signaling Inhibits Lipopolysaccharide-Stimulated Tumor Necrosis Factor α Production in Macrophages , 2013, PloS one.

[3]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[4]  C. Glass,et al.  Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. , 2010, Molecular cell.

[5]  S. Vacher,et al.  Protein Kinase D1 Regulates Erα-positive Breast Cancer Cell Growth Response To 17β­estradiol And Contributes To Poor Prognosis In Patients , 2014 .

[6]  G. Sauter,et al.  Tissue inhibitor of metalloproteinase-4 is elevated in early-stage breast cancers with accelerated progression and poor clinical course. , 2009, The American journal of pathology.

[7]  Xu-wen Liu,et al.  Novel functions of TIMPs in cell signaling , 2006, Cancer and Metastasis Reviews.

[8]  W. Carney,et al.  Serum TIMP-1 and response to the aromatase inhibitor letrozole versus tamoxifen in metastatic breast cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  K. Brew,et al.  Tissue inhibitors of metalloproteinases: evolution, structure and function. , 2000, Biochimica et biophysica acta.

[10]  W. Stetler-Stevenson.  Tissue Inhibitors of Metalloproteinases In Cell Signaling , 2008 .

[11]  N. Stanietsky,et al.  Microenvironment and Immunology MiR-10 b Downregulates the Stress-Induced Cell Surface MoleculeMICB , a Critical Ligand for Cancer Cell Recognition by Natural Killer Cells , 2012 .

[12]  Isabelle Salmon,et al.  TIMP-4 and CD63: new prognostic biomarkers in human astrocytomas , 2010, Modern Pathology.

[13]  J. Meléndez-Zajgla,et al.  Tissue Inhibitor of Metalloproteinase-4 Triggers Apoptosis in Cervical Cancer Cells , 2015, PloS one.

[14]  M. Ponglikitmongkol,et al.  17β-Estradiol suppresses MHC class I chain-related B gene expression via an intact GC box. , 2013, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[15]  J. Meléndez-Zajgla,et al.  Tissue inhibitor of metalloproteinases‐4 (TIMP‐4) regulates stemness in cervical cancer cells , 2016, Molecular carcinogenesis.

[16]  J. Meléndez-Zajgla,et al.  Tissue Inhibitor of Metalloproteinases-4. The road less traveled , 2008, Molecular Cancer.

[17]  Lorenzo Galluzzi,et al.  Metabolic control of cell death , 2014, Science.

[18]  G. Greene,et al.  RAC3 is a promigratory co-activator of ERα , 2010, Oncogene.

[19]  J. Meléndez-Zajgla,et al.  Tissue inhibitor of metalloproteinases-4 is expressed in cervical cancer patients. , 2005, Anticancer research.

[20]  P. Eriksson,et al.  Endometrial TIMP-4 mRNA is high at midcycle and in hyperplasia, but down-regulated in malignant tumours. Coordinated expression with MMP-26. , 2004, Molecular human reproduction.

[21]  H. Nam,et al.  TNF alpha-induced down-regulation of estrogen receptor alpha in MCF-7 breast cancer cells. , 2008, Molecules and cells.

[22]  James W. Smyth,et al.  TGF-β-induced activation of mTOR complex 2 drives epithelial–mesenchymal transition and cell invasion , 2012, Journal of Cell Science.

[23]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[24]  Rakesh Kumar,et al.  Derailed estrogen signaling and breast cancer: an authentic couple. , 2013, Endocrine reviews.