Accession Number:

ADA510053

Title:

Mechanistic Basis of Calmodulin Mediated Estrogen Receptor Alpha Activation and Antiestrogen Resistance

Descriptive Note:

Annual rept. 15 May 2008-14 May 2009

Corporate Author:

GEORGIA UNIV RESEARCH FOUNDATION INC ATHENS

Report Date:

2009-06-01

Pagination or Media Count:

42.0

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.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE