Regulation of estrogen-mediated cell survival and proliferation by p160 coactivators.
Surgery
; 136(2): 346-54, 2004 Aug.
Article
em En
| MEDLINE
| ID: mdl-15300201
ABSTRACT
BACKGROUND:
Estrogen receptor (ER) activity is dependent on coactivator (CoA) proteins. The role of CoA-ER interactions in breast cancer apoptosis remains unexplored.METHODS:
Expression vectors for the p160 CoA genes NCOA-1, NCOA-2, or NCOA-3 were transiently transfected into MCF-7 cells. Cell survival was determined by viability and clonogenic survival assays. Effects of CoA expression on estrogen (E2) signaling were determined by estrogen response element (ERE)-luciferase reporter-gene assay. Clonogenic and reporter-gene survival assays were used to examine the molecular inhibition of CoA function (dominant inhibitory [DI]-decoy-CoA) on cell survival. Statistical significance was established at the P < .05 level.RESULTS:
Overexpression of NCOA-1, NCOA-2, and NCOA-3 enhanced E2-mediated gene expression by 3.17 +/- 0.51-, 2.33 +/- 0.8-, and 3.65 +/- 0.65-fold, respectively, and enhanced cell survival by suppressing tumor necrosis factor alpha (TNF-alpha)-induced cell death from 80.23% +/- 2.66% viability to 101.5% +/- 8.9%, 86.9% +/- 9.9%, and 95.7% +/- 8.5% viability, respectively. NCOA-1 enhancement of cell survival occurred via suppression of TNF-alpha-induced apoptosis as confirmed by viability and morphologic evaluation. Clonogenic survival and E2-stimulated colony formation in MCF-7 cells were suppressed by expression of DI-decoy-NCOA-1 and DI-decoy-NCOA-3 to 34.4% +/- 7.4% and 54% +/- 5.4% of vector control, but not DI-decoy-NCOA-2.CONCLUSIONS:
Overexpression of NCOA-1 and NCOA-3 exerted potent survival effects in breast carcinoma cells. Use of DI-CoA constructs enhanced TNF-alpha-induced cell death and abrogated E2-induced survival. Inhibition of CoA proteins represents a mechanism for enhancing sensitivity therapies in breast carcinoma.
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Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Neoplasias da Mama
/
Transativadores
/
Estrogênios
Limite:
Female
/
Humans
Idioma:
En
Revista:
Surgery
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Estados Unidos