Alan Prem Kumar
National University of Singapore
Singapore
Title: DEAD-box RNA Helicase DP103 as a Biomarker for Therapeutic Response to Docetaxel
Biography
Biography: Alan Prem Kumar
Abstract
Resistance to chemotherapy offers limitations to the treatment of breast cancer. This has generated an increased interest in identifying new biomarkers to better predict drug responses among patients. Gene expression analysis and immuno-histochemistry profiling of patient samples, randomized to a combination of docetaxel and doxorubicin, revealed a chemotherapy induced decrease in DP103 expression among responders, and an increase among non-responders. These clinical findings were also validated in-vitro, using representative cell lines to mimic responders, and their corresponding drug resistant subtypes as non-responders. Upon stratification by the receptor status, the predictive value of DP103 was only observed in patient samples and cell lines with ERα-positive status and not with ERα-negative status. The observed changes in DP103 expression was well correlated to a similar drug induced change in the expression of ERα; raising a possibility of a cross-talk between DP103 and ERα. ChIP-Seq analysis and estradiol-stimulation studies validated DP103 to be an estrogen-inducible gene. Interestingly, DP103 was also indentified as a potential modulator of ERα transcriptional activity. Silencing DP103 inhibited estradiol-induced ERα DNA-binding activity, expression of ERα target genes, cell growth and colony forming ability. These findings summarise a novel role of DP103 in acquired drug resistance; presenting a potential surrogate biomarker for predicting drug response in breast cancer. In addition, we have also uncovered a positive feed-forward loop between DP103 and ERα that could regulate the activity of the latter in ERα positive breast cancer.