Inhibition of androgen receptor increases sensitivity of TRAIL‐induced apoptosis via upregulation of death receptor 5 in breast cancer

Abstract

Background and objectiveTRAIL (TNF‐related apoptosis‐inducing ligand) is a promising cancer therapeutic agent due to its minimal toxicity to normal tissues and remarkable apoptotic activity in tumors. However, most breast cancer cells are resistant to TRAIL‐induced apoptosis. Our objectives were to investigate the underlying molecular mechanisms of TRAIL‐resistance and to develop strategies to overcome such resistance.MethodsTo identify modulators of TRAIL‐induced apoptosis, we carried out a genomewide siRNA screen. To validate the screening result, we either silenced or overexpressed the identified genes in various breast cancer cells, and changes in TRAIL‐induced cell apoptosis were determined by flow cytometry and caspase‐dependent Poly (ADP‐ribose) polymerase (PARP) cleavage in vitro and in an orthotopic xenograft mouse model. Expression of TRAIL receptor, Death Receptor 5 (DR5) was analyzed by western blot. Finally, we investigated whether small molecules targeting the identified genes improve the effectiveness of TRAIL‐therapy.ResultsWe unexpectedly identified androgen receptor (AR) to be responsible for TRAIL resistance. While AR is classically viewed as the key factor in prostate cancer progression, we found that AR expression levels were markedly elevated in human invasive breast cancer specimens including triple‐negative breast cancers (TNBC) that are highly aggressive with poor prognosis. Importantly, breast cancer cell lines express different levels of AR that correlated with their TRAIL resistance. AR overexpression in MDA‐MB‐231 and MDA‐MB‐436 cells suppressed the TRAIL sensitivity whereas knockdown of AR by siRNAs rendered MCF‐7 and MDA‐MB‐453 cells sensitive to TRAIL‐induced apoptosis. AR overexpression also induced TRAIL resistance in breast tumors in vivo. Further, we observed an upregulation of the DR5 expression in breast cancer cells following the silence or inhibition of AR by its antagonists Casodex and MDV3100. Treatment with AR antagonists increased TRAIL‐induced apoptosis and blocked MDA‐MB‐453 cell growth.ConclusionAR signaling suppresses TRAIL‐induced breast cancer cell apoptosis, in part, by suppressing DR5 expression. A combination of AR antagonists together with TRAIL may be a novel and effective therapy for breast cancer.Support or Funding InformationThe project supported by the National Institutes of Health Grants R21CA193271 and R01HL116849This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.