Mechanistic Basis of Calmodulin Mediated Estrogen Receptor Alpha Activation and Antiestrogen Resistance
Abstract
Estrogen receptor alpha (ERalpha) is the principle chemotherapeutic target for estrogen dependent breast cancers. Calmodulin (CaM) is an obligatory ERalpha activator. Moreover, antiestrogens (tamoxifen) bind tightly to CaM, and some therapeutic benefits of antiestrogens for breast cancers are hypothesized to derive from this interaction. The purpose and scope of the research is to define the structural requisites of ERalpha activation by CaM and the relationship between tamoxifen binding to CaM, CaM oxidation and antiestrogen resistance. We have localized and refined our understanding of the CaM binding sites on ERalpha. We demonstrated that the high affinity CaM binding region of ERalpha forms both helical and random coil structure when bound to CaM. We demonstrated that tamoxifen, hydroxytamoxifen and raloxifene binding to CaM are eliminated when the methionine residues of CaM are oxidized. We determined that oxidation of the methionine residues in CaM does not eliminate CaM binding to ERalpha. The results suggest a mechanism whereby antiestrogen resistance is exacerbated by oxidative stress.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2009
- Accession Number
- ADA510053
Entities
People
- Carrie E. Jolly
- Jeffrey L. Urbauer
- Ramona J. Bieber-urbauer
Organizations
- University of Georgia Research Foundation