Androgen Receptor Splice Variants and Resistance to Taxane Chemotherapy
Annual rept. 29 Sep 2014-28 Sep 2015
TULANE UNIV NEW ORLEANS LA
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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.
- Medicine and Medical Research