Peptide Antiestrogens for Human Breast Cancer Therapy
Abstract
Growth of breast cells is regulated by estrogens. This hormone binds receptors present in 60-70% of breast cancers. Estrogen receptor alpha (ER) is a phosphoprotein that regulates transcription and growth by binding to estrogen response elements (ERE) in DNA. Inactive ER is a monomer that forms a dimer on estrogen-induced phosphorylation. This signaling complex recruits steroid receptor coactivator proteins, such as SRC-I, that are essential for growth. Transcriptional activity of ER is regulated by distinct conformational states resulting from ligand binding. Peptides derived from the interacting sites of ER proteins may selectively inhibit ER signaling and function as antiestrogens. To test this hypothesis, we synthesized small peptides that mimic a highly conserved ER sequence including tyrosine-537 and surrounding leucine residues. Peptide antiestrogens, but not control peptides, blocked association of ER with SRC-1, and, in gel mobility shift assays, disrupted binding of ER to (P-32)-ERE. Using in vitro studies with breast cells, treatment with estradiol stimulated cell growth 4-fold by 72 h. This effect of estrogen was blocked by pre-treatment with 10(exp -9) M peptide antiestrogens conjugated with Antennapedia carrier but not by control peptides. In in vivo tumor xenograft experiments, treatment of nude mice with peptide antiestrogens showed significant activity in arresting growth of estrogen-dependent breast tumors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2000
- Accession Number
- ADA385808
Entities
People
- Richard Pietras
Organizations
- University of California, Los Angeles