Linked Life Data

21676886

Source:http://linkedlifedata.com/resource/pubmed/id/21676886

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
15
pubmed:dateCreated
2011-8-1
pubmed:abstractText
Resistance to platinum-based chemotherapy develops in the majority of patients with epithelial ovarian cancer (EOC). Platinum compounds form electrophilic intermediates that mediate DNA cross-linking and induce double-strand DNA breaks. Because the cellular response to electrophilic xenobiotics is partly mediated by Keap1-Nrf2 pathway, we evaluated the presence of Kelch-like ECH-associated protein 1 (Keap1) mutations and NF-E2-related factor 2 (Nrf2) pathway activation in EOC and correlated these with platinum resistance and clinical outcome. Nrf2 immunohistochemistry revealed nuclear localization (a surrogate of pathway activation) in over half of EOC patient specimens examined, with more common occurrence in the clear cell EOC subtype. Quantitative real-time PCR revealed that Nrf2 target genes were upregulated in tumors with nuclear positivity for Nrf2. Microarray analysis also showed upregulation of Nrf2 target genes in clear cell EOCs compared with other EOC subtypes. In addition, Keap1 sequence analysis revealed genetic mutations in 29% of clear cell samples and 8% of nonclear cell tumors. RNAi-mediated knockdown of Keap1 was associated with Nrf2 pathway activation and resistance to carboplatin in vitro. Importantly, patients with evidence of Nrf2 pathway activation had fewer complete clinical responses to platinum-based therapy, were enriched for platinum resistance, and had shorter median overall survival compared with those who did not show evidence of Nrf2 pathway activation. Our findings identify Keap1 mutations in EOC and they suggest a previously unrecognized role for the Keap1-Nrf2 pathway in mediating chemotherapeutic responses in this disease.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1538-7445
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
71
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5081-9
pubmed:meshHeading
pubmed-meshheading:21676886-Adenocarcinoma, Clear Cell, pubmed-meshheading:21676886-Antineoplastic Agents, Alkylating, pubmed-meshheading:21676886-Carboplatin, pubmed-meshheading:21676886-Carcinoma, pubmed-meshheading:21676886-Cell Line, Tumor, pubmed-meshheading:21676886-DNA, Neoplasm, pubmed-meshheading:21676886-DNA Mutational Analysis, pubmed-meshheading:21676886-Drug Resistance, Neoplasm, pubmed-meshheading:21676886-Female, pubmed-meshheading:21676886-Gene Expression Profiling, pubmed-meshheading:21676886-Humans, pubmed-meshheading:21676886-Intracellular Signaling Peptides and Proteins, pubmed-meshheading:21676886-Kaplan-Meier Estimate, pubmed-meshheading:21676886-NF-E2-Related Factor 2, pubmed-meshheading:21676886-Neoplasm Proteins, pubmed-meshheading:21676886-Organoplatinum Compounds, pubmed-meshheading:21676886-Ovarian Neoplasms, pubmed-meshheading:21676886-Proportional Hazards Models, pubmed-meshheading:21676886-RNA, Small Interfering, pubmed-meshheading:21676886-RNA Interference, pubmed-meshheading:21676886-Sequence Analysis, DNA, pubmed-meshheading:21676886-Signal Transduction
pubmed:year
2011
pubmed:articleTitle
Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer.
pubmed:affiliation
Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. pkonstan@bidmc.harvard.edu
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't