Linked Life Data

21057537

Source:http://linkedlifedata.com/resource/pubmed/id/21057537

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2011-3-3
pubmed:abstractText
Fulvestrant is a selective estrogen receptor downregulator (SERD) and highly effective antagonist to hormone-sensitive breast cancers following failure of previous tamoxifen or aromatase inhibitor therapies. However, after prolonged fulvestrant therapy, acquired resistance eventually occurs in the majority of breast cancer patients, due to poorly understood mechanisms. To examine a possible role(s) of aberrantly expressed microRNAs (miRNAs) in acquired fulvestrant resistance, we compared antiestrogen-resistant and -sensitive breast cancer cells, revealing the overexpression of miR-221/222 in the SERD-resistant cell lines. Fulvestrant treatment of estradiol (E2)- and fulvestrant-sensitive MCF7 cells resulted in increased expression of endogenous miR-221/222. Ectopic upregulation of miR-221/222 in estrogen receptor-? (ER?)-positive cell lines counteracted the effects of E2 depletion or fulvestrant-induced cell death, thus also conferring hormone-independent growth and fulvestrant resistance. In cells with acquired resistance to fulvestrant, miR-221/222 expression was essential for cell growth and cell cycle progression. To identify possible miR-221/222 targets, miR-221- or miR-222- induced alterations in global gene expression profiles and target gene expression at distinct time points were determined, revealing that miR-221/222 overexpression resulted in deregulation of multiple oncogenic signaling pathways previously associated with drug resistance. Activation of ?-catenin by miR-221/222 contributed to estrogen-independent growth and fulvestrant resistance, whereas TGF-?-mediated growth inhibition was repressed by the two miRNAs. This first in-depth investigation into the role of miR-221/222 in acquired fulvestrant resistance, a clinically important problem, demonstrates that these two 'oncomirs' may represent promising therapeutic targets for treating hormone-independent, SERD-resistant breast cancer.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1476-5594
pubmed:author
pubmed:issnType
Electronic
pubmed:day
3
pubmed:volume
30
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1082-97
pubmed:meshHeading
pubmed-meshheading:21057537-Antineoplastic Agents, pubmed-meshheading:21057537-Breast Neoplasms, pubmed-meshheading:21057537-Cell Line, Tumor, pubmed-meshheading:21057537-Cell Proliferation, pubmed-meshheading:21057537-Drug Resistance, Neoplasm, pubmed-meshheading:21057537-Estradiol, pubmed-meshheading:21057537-Estrogen Antagonists, pubmed-meshheading:21057537-Estrogen Receptor alpha, pubmed-meshheading:21057537-Female, pubmed-meshheading:21057537-Gene Expression Regulation, Neoplastic, pubmed-meshheading:21057537-Humans, pubmed-meshheading:21057537-MicroRNAs, pubmed-meshheading:21057537-Oligonucleotide Array Sequence Analysis, pubmed-meshheading:21057537-Selective Estrogen Receptor Modulators, pubmed-meshheading:21057537-Signal Transduction, pubmed-meshheading:21057537-Transforming Growth Factor beta, pubmed-meshheading:21057537-Up-Regulation, pubmed-meshheading:21057537-beta Catenin
pubmed:year
2011
pubmed:articleTitle
MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways.
pubmed:affiliation
Interdisciplinary Biochemistry Graduate Program, Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural