A Novel Molecular Target for Breast Cancer Prevention and Treatment
Abstract
Induction of apoptosis is a plausible approach for developing new cancer therapies. A class of synthetic retinoids related to 6-3-(1-ADAMANTLYL)-4-HYDROXYPHENYL-2-naphthalene carboxylic acid (AHPN/CD437) potently induce apoptosis of both hormone-dependent and - independent breast cancers. We previously reported that apoptotic effects of AHPN/CD437 are mediated by mitochondrial targeting of orphan nuclear receptor TR3. In the past year, we have studied the mechanisms by which TR3 migrates from the nucleus to the cytoplasm and by which TR3 targets mitochondria. Our results demonstrate that the migration of TR3 from the nucleus to the cytoplasm requires retinoid X receptor (RXR) through their unique heterodimerization and is regulated by RXR ligands. We have also identified a nuclear export sequence in the RXR, which is required for its cytoplasmic localization. Furthermore, we have found that TR3 targets mitochondria through its interaction with Bcl- 2 that resides at the outer mitochondrial membrane. The interaction converts Bcl-2 from an anti-apoptotic to a pro-apoptotic molecule. Our results not only enhance our understanding of the molecular mechanism by which TR3 exerts its apoptotic effects in breast cancer cells but also provide novel approaches to induce apoptosis ob Bcl-2-expressing breast cancer cells by using RXR ligands.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2003
- Accession Number
- ADA420313
Entities
People
- Xiao-kun Zhang
Organizations
- Sanford Burnham Prebys Medical Discovery Institute