Linked Life Data

20164500

Source:http://linkedlifedata.com/resource/pubmed/id/20164500

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2010-2-18
pubmed:abstractText
Identification of molecular mechanisms responsible for brain metastatic breast cancer (BMBC) is imperative to develop novel therapies. However, current understanding of the molecular circuitry that governs BMBC dissemination remains fragmentary. Heparanase (HPSE) is the only functional mammalian endoglycosidase whose activity correlates with cancer metastasis, angiogenesis, and the reduced postoperative survival of cancer patients, making it an active target for anticancer therapeutics. We hypothesized that human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) activation promotes HPSE function in human BMBC. To address this, we examined HPSE content, activity, and intracellular trafficking in a HER2/EGFR-expressing BMBC model system and show that HPSE is present, functional, and correlates with HER2 status. Further, we showed that EGF induced nucleolar translocation of HPSE in these cells in a dose- and time-dependent manner upon activation of HER2/EGFR. Knockdowns of HER2/EGFR by small interference RNA abolished EGF-induced HPSE nucleolar translocalization. It was also noted that nucleolar HPSE modulates DNA topoisomerase I (Topo I), an enzyme that is highly present in nucleoli, essential for DNA replication and transcription in a variety of tumors, and inhibited by heparan sulfate. Evidence is provided that HPSE can regulate Topo I activity, which subsequently affects BMBC cell proliferation. Finally, we showed that the nucleolar presence of HPSE with Topo I colocalization is detected only in HER2-overexpressing BMBC patient specimens. Altogether, these findings support the notion that HPSE is a critical downstream target of HER2 mechanisms driving BMBC and is potentially relevant for BMBC therapeutic interventions.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1557-3125
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
8
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
278-90
pubmed:meshHeading
pubmed-meshheading:20164500-Active Transport, Cell Nucleus, pubmed-meshheading:20164500-Animals, pubmed-meshheading:20164500-Brain Neoplasms, pubmed-meshheading:20164500-Breast Neoplasms, pubmed-meshheading:20164500-Carcinoma, pubmed-meshheading:20164500-Cell Line, Tumor, pubmed-meshheading:20164500-Cell Nucleolus, pubmed-meshheading:20164500-DNA Topoisomerases, Type I, pubmed-meshheading:20164500-Down-Regulation, pubmed-meshheading:20164500-Epidermal Growth Factor, pubmed-meshheading:20164500-Female, pubmed-meshheading:20164500-Gene Expression Regulation, Neoplastic, pubmed-meshheading:20164500-Glucuronidase, pubmed-meshheading:20164500-Humans, pubmed-meshheading:20164500-Mice, pubmed-meshheading:20164500-Mice, Nude, pubmed-meshheading:20164500-Models, Biological, pubmed-meshheading:20164500-Neoplasm Metastasis, pubmed-meshheading:20164500-Protein Transport, pubmed-meshheading:20164500-RNA Interference, pubmed-meshheading:20164500-Receptor, erbB-2, pubmed-meshheading:20164500-Signal Transduction
pubmed:year
2010
pubmed:articleTitle
Epidermal growth factor-induced heparanase nucleolar localization augments DNA topoisomerase I activity in brain metastatic breast cancer.
pubmed:affiliation
Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural