Peptide Antiestrogens for Human Breast Cancer Therapy

摘要

Estrogen binds specific receptors present in 70% of breast cancers. 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 diners on estrogen-induced phosphorylation ER transcriptional activity is regulated by distinct conformational states resulting from ligand binding, and the induced complex recruits steroid receptor coactivator proteins, such as SRC-1, that are essential for growth. Peptides modeled from interacting sites of ER may selectively inhibit ER signals and act as antiestrogens. To test this hypothesis, we made small peptides to mimic highly conserved ER sequence at tyrosine-537 and surrounding leucine residues. Peptide antiestrogens, but not control peptides, block ER association with SRC-l and disrupt binding of ER to ERR. In in vitro studies, estradiol stimulates breast cell growth, and this estrogen effect is blocked by peptide antiestrogens conjugated with Antennapedia carrier, but not controls. Using in vivo tumor xenografts, treatment 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. Thus, we have prepared more lipid-like, peptidomimetric derivatives that function similarly but may be easier to use in the clinic.