Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
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Drug
Enzyme
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Target Concepts:
Gene/Protein
Disease
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Query: UMLS:C0278488 (
metastatic breast cancer
)
7,812
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Human
kallikrein-related peptidase 6
(
KLK6
) was cloned as a putative class II tumor suppressor based on its inactivated expression in
metastatic breast cancer
. Here, we investigated the mechanism(s) underlying the silencing of
KLK6
gene in
metastatic breast cancer
and its putative implications for tumor progression. We present evidence that tumor-specific loss of
KLK6
expression is due to hypermethylation of specific CpGs located in the
KLK6
proximal promoter. Methylation-dependent binding of methyl CpG-binding protein 2 and the formation of repressive chromatin mediated by localized histone deacetylation are critical components of
KLK6
silencing in breast tumors. Re-expression of
KLK6
in nonexpressing MDA-MB-231 breast tumor cells by stable cDNA transfection resulted in marked reversal of their malignant phenotype, manifested by lower proliferation rates and saturation density, marked inhibition of anchorage-independent growth, reduced cell motility, and their dramatically reduced ability to form tumors when implanted in severe combined immunodeficiency mice. Interestingly, inhibition of tumor growth was observed at physiologic concentrations of
KLK6
, but not when
KLK6
was highly overexpressed, as observed in a subset of breast tumors. Differential proteomic profiling revealed that
KLK6
re-expression results in significant down-regulation of vimentin which represents an established marker of epithelial-to-mesenchymal transition of tumor cells and in concomitant up-regulation of calreticulin and epithelial markers cytokeratin 8 and 19, indicating that
KLK6
may play a protective role against tumor progression that is likely mediated by inhibition of epithelial-to-mesenchymal transition. We suggest that
KLK6
is an epigenetically regulated tumor suppressor in human breast cancer and provide ways of pharmacologic modulation.
...
PMID:A tumor-protective role for human kallikrein-related peptidase 6 in breast cancer mediated by inhibition of epithelial-to-mesenchymal transition. 1938 23
