Linked Life Data

17473282

Source:http://linkedlifedata.com/resource/pubmed/id/17473282

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2007-6-27
pubmed:abstractText
Acquired resistance to endocrine therapy represents a major clinical obstacle to the successful management of estrogen-dependent breast cancers expressing estrogen receptor alpha (ERalpha). Because a switch from ligand-dependent to ligand-independent activation of ERalpha-regulated breast cancer cell growth and survival may define a path to endocrine resistance, enhanced mechanistic insight concerning the ligand-independent fate and function of ERalpha, including a more complete inventory of its ligand-independent cofactors, could identify novel markers of endocrine resistance and possible targets for therapeutic intervention in breast cancer. Here, we identify the deleted in breast cancer 1 gene product DBC-1 (KIAA1967) to be a principal determinant of unliganded ERalpha expression and survival function in human breast cancer cells. The DBC-1 amino terminus binds directly to the ERalpha hormone-binding domain both in vitro and in vivo in a strict ligand-independent manner. Furthermore, like estrogen, the antiestrogens tamoxifen and ICI 182,780 (7alpha,17beta-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol) disrupt the DBC-1/ERalpha interaction, thus revealing the DBC-1/ERalpha interface to be a heretofore-unrecognized target of endocrine compounds commonly used in hormonal therapy. Notably, RNA interference-mediated DBC-1 depletion reduces the steady-state level of unliganded but not liganded ERalpha protein, suggesting that DBC-1 may stabilize unliganded ERalpha by virtue of their direct association. Finally, DBC-1 depletion promotes hormone-independent apoptosis of ERalpha-positive, but not ERalpha-negative, breast cancer cells in a manner reversible by endocrine agents that disrupt the DBC-1/ERalpha interaction. Collectively, these findings establish a principal biological function for DBC-1 in the modulation of ERalpha expression and hormone-independent breast cancer cell survival.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0888-8809
pubmed:author
pubmed:issnType
Print
pubmed:volume
21
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1526-36
pubmed:dateRevised
2008-3-24
pubmed:meshHeading
pubmed-meshheading:17473282-Adaptor Proteins, Signal Transducing, pubmed-meshheading:17473282-Base Sequence, pubmed-meshheading:17473282-Binding Sites, pubmed-meshheading:17473282-Breast Neoplasms, pubmed-meshheading:17473282-Cell Line, Tumor, pubmed-meshheading:17473282-Cell Survival, pubmed-meshheading:17473282-DNA Primers, pubmed-meshheading:17473282-Estrogen Receptor Modulators, pubmed-meshheading:17473282-Estrogen Receptor alpha, pubmed-meshheading:17473282-Female, pubmed-meshheading:17473282-HeLa Cells, pubmed-meshheading:17473282-Humans, pubmed-meshheading:17473282-Ligands, pubmed-meshheading:17473282-Neoplasm Proteins, pubmed-meshheading:17473282-Protein Binding, pubmed-meshheading:17473282-Protein Structure, Tertiary, pubmed-meshheading:17473282-RNA, Small Interfering, pubmed-meshheading:17473282-RNA Interference
pubmed:year
2007
pubmed:articleTitle
Modulation of estrogen receptor alpha protein level and survival function by DBC-1.
pubmed:affiliation
Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245-3207, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural