Peptide Antiestrogens for Human Breast Cancer Therapy
Abstract
Estrogen binds specific receptors that are present in 60-70% of breast cancers. The estrogen receptor (ER) is a phosphoprotein that regulates transcription and growth by binding estrogen response elements (ERE) in DNA. Inactive ER is a monomer that forms dimers on estrogen-induced phosphorylation. Transcriptional activity of ER is regulated by distinct conformational states resulting from ligand binding, and the induced signal complex recruits steroid receptor coactivator proteins, such as SRC- 1, that are essential for growth. Peptides modeled from interacting sites of ER proteins may selectively inhibit ER signaling and act as antiestrogens. To test this hypothesis, we prepared small peptides to mimic a highly conserved ER sequence including tyrosine-537 and surrounding leucine residues. Peptide antiestrogens, but not control peptides, block ER association with SRC-1 and disrupt binding of ER to ERE. In in vitro studies, estradiol stimulates breast cell growth, and this estrogen effect is blocked by peptide antiestrogens conjugated with Antennapedia carrier but not by control peptides. Using in vivo tumor xenografts, treatment of nude mice with peptide antiestrogens shows significant activity in arresting growth of estrogen-dependent breast tumors. This work provides target validation but also shows that peptide drugs are difficult to administer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADA396963
Entities
People
- Richard J. Pietras
Organizations
- University of California, Los Angeles