Coactivator Requirements for Serm Action
Abstract
Estrogen receptor alpha- (ER(alpha)) mediates the effects of estrogens in breast cancer development and growth via transcriptional regulation of target genes. Tamoxifen can antagonize ER(alpha) activity and has been used in breast cancer therapy. The molecular determinants of tamoxifen action are not completely understood, but the availability of ER coregulators is thought to play a role. Tamoxifen-bound ER(alpha) associates with nuclear receptor corepressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) at certain target genes. To determine if these corepressors are required for tamoxifen- mediated repression, their expression levels were reduced by RNA interference and the effects on tamoxifen action in breast cancer cells were measured. Silencing both corepressors led to tamoxifen-stimulated cell cycle progression without activation of the 0-myc, cyclin Dl, or SDF-1 genes, which play a role in estrogen-induced cell growth. By contrast, expression of X-box binding protein 1 (XBP-1) was markedly elevated upon silencing N-CoR and SMRT and treating with tamoxifen. These results indicate that N-CoR and SMRT may influence tamoxifen action on a subset of genes involved in ER(alpha) function and cell proliferation. These findings help to further elucidate mechanisms underlying tamoxifen action that may be relevant to understanding tamoxifen-stimulated tumor growth.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2005
- Accession Number
- ADA441279
Entities
People
- Erika K. Keeton
Organizations
- Dana–Farber Cancer Institute