The Role of Estrogen Receptor a K303R Mutation in Breast Cancer Metastasis
Abstract
Last year we reported that MTAl-Ll is an ER-corepressor but unable to repress the activity of the naturally occurred K3O3R ER mutant. We report here that MTAl-Ll could deacetylate the p3OO acetylated ER, probably via its associated HDAC activity. Also we found that a EDAC inhibitor reverses MTAl-Ll inhibited ER activity, suggesting that MTAl-Ll inhibit ER activity through EDACs. Later we determined that two other corepressors, NcoR and BRCAl, which also associated with HDAC, can not repress the K3O3R activity, suggesting that the hypoacetylated state of K3O3R might account for its ligand hypersensitivity. However, using different mutations in the KC3O3 sites, we demonstrated that hypoacetylation is not sufficient for K3O3R ER hypersensitivity, suggesting that other signals such as kinases could play a role. In deed, we found that K3O3R mutant makes ER Ser3O5 a more efficient target for both Protein Kinase A(PKA) as well as p2l-activated kinase 1(PAKl) through both in vitro and in vivo kinases assays. Also, phosphorylation of Ser3O5 can inhibit K303 acetylation by p3OO. In addition, mimic Ser3O5 phosphorylation by Ser3O5Asp Inutation confers ER hypersensitive to estrogen. In summary, our data demonstrated that K3O3R alters ER regulation by multiple signals.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2004
- Accession Number
- ADA427030
Entities
People
- Suzanne Fuqua
- Yukun Cui
Organizations
- Baylor College of Medicine