Androgen Receptor Splice Variants and Resistance to Taxane Chemotherapy
Abstract
During the first reporting period, we have made significant progress in understanding the fundamental difference in nuclear translocation mechanism between full-length androgen receptor (AR-FL) and AR splice variants (AR-Vs). We found that the AR-FL is associated with the microtubule cytoskeleton and is transported by the microtubules prior to its nuclear translocation. On the other hand, AR-V7 and ARv567es have weak microtubule-binding activities and use a microtubule-independent mechanism for intracellular transport. Through a series of deletion analyses, we have mapped the microtubule-binding activity to two regions in the AR ligand-binding domain. In addition, we found that AR-V7 and ARv567es interfere with docetaxelmediated AR-FL cytoplasmic retention, possibly by forming heterodimers with AR-FL and decreasing its microtubule-binding activity. These findings provide evidence that constitutively active AR-Vs maintain the AR signaling axis by evading the inhibitory effects of microtubule-targeting agents, suggesting that these AR-Vs play a role in resistance to taxane chemotherapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2015
- Accession Number
- ADA626032
Entities
People
- Haitao Zhang
Organizations
- Tulane University of Louisiana