RGD Reference Report - KLF8 promotes human breast cancer cell invasion and metastasis by transcriptional activation of MMP9. - Rat Genome Database

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KLF8 promotes human breast cancer cell invasion and metastasis by transcriptional activation of MMP9.

Authors: Wang, X  Lu, H  Urvalek, AM  Li, T  Yu, L  Lamar, J  DiPersio, CM  Feustel, PJ  Zhao, J 
Citation: Wang X, etal., Oncogene. 2011 Apr 21;30(16):1901-11. doi: 10.1038/onc.2010.563. Epub 2010 Dec 13.
RGD ID: 8547839
Pubmed: PMID:21151179   (View Abstract at PubMed)
PMCID: PMC3952074   (View Article at PubMed Central)
DOI: DOI:10.1038/onc.2010.563   (Journal Full-text)

Epithelial to mesenchymal transition (EMT) and extracellular matrix degradation are critical for the initiation and progression of tumor invasion. We have recently identified Kruppel-like factor 8 (KLF8) as a critical inducer of EMT and invasion. KLF8 induces EMT primarily by repressing E-cadherin transcription. However, how KLF8 promotes invasion is unknown. Here, we report a novel KLF8-to- matrix metalloproteinase (MMP)9 signaling that promotes human breast cancer invasion. To identify the potential KLF8 regulation of MMPs in breast cancer, we established two inducible cell lines that allow either KLF8 overexpression in MCF-10A or knockdown in MDA-MB-231 cells. KLF8 overexpression induced a strong increase in MMP9 expression and activity as determined by quantitative real-time PCR and zymography. This induction was well correlated with the MMP inhibitor-sensitive Matrigel invasion. Conversely, KLF8 knockdown caused the opposite changes that could be partially prevented by MMP9 overexpression. Promoter-reporter assays and chromatin and oligonucleotide precipitations determined that KLF8 directly bound and activated the human MMP9 gene promoter. Three-dimensional (3D) glandular culture showed that KLF8 expression disrupted the normal acinus formation, which could be prevented by the MMP inhibitor, whereas KLF8 knockdown corrected the abnormal 3D architecture, which could be protected by MMP9 overexpression. KLF8 knockdown promoted MDA-MB-231 cell aggregation in suspension culture, which could be prevented by MMP9 overexpression. KLF8 knockdown inhibited the lung metastasis of MDA-MB-231 cells in nude mice. Immunohistochemical staining strongly correlated the co-expression of KLF8 and MMP9 with the patient tumor invasion, metastasis and poor survival. Taken together, this work identified the KLF8 activation of MMP9 as a novel and critical signaling mechanism underlying human breast cancer invasion and metastasis.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Breast Neoplasms disease_progressionIEP 8547839 RGD 
Breast Neoplasms disease_progressionISOMMP9 (Homo sapiens)8547839; 8547839 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mmp9  (matrix metallopeptidase 9)

Genes (Mus musculus)
Mmp9  (matrix metallopeptidase 9)

Genes (Homo sapiens)
MMP9  (matrix metallopeptidase 9)


Additional Information