Breast Cancer Stem-Like Cells Are Inhibited by a Non-Toxic Aryl Hydrocarbon Receptor Agonist 英文参考文献.docVIP

BreastCancerStem-LikeCellsAreInhibitedbyaNon- ToxicArylHydrocarbonReceptorAgonist Ge′raldJ.Prud’homme1,2*,YelenaGlinka1,2,AnnaToulina1,2,OlgaAce1,2 ,Venkateswaran Subramaniam1,2,SergeJothy1,2 1Department of Laboratory Medicine and Li Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto, Canada, 2Department of Laboratory Medicine and Pathobiology,UniversityofToronto,Toronto,Canada Abstract Background:Cancerstemcells(CSCs)haveincreasedresistancetocancerchemotherapy.Theycanbeenrichedasdrug- survivingCSCs(D-CSCs)bygrowthwithchemotherapeuticdrugs,and/orbysortingofcellsexpressingCSCmarkerssuchas aldehyde dehydrogenase-1 (ALDH). CSCs form colonies in agar, mammospheres in low-adherence cultures, and tumors followingxenotransplantationinScidmice.Wehypothesizedthattranilast,anon-toxicorallyactivedrugwithanti-cancer activities,wouldinhibitbreastCSCs. Methodology/Findings: We examined breast cancer cell lines or D-CSCs generated by growth of these cells with mitoxantrone. Tranilast inhibited colony formation, mammosphere formation and stem cell marker expression. Mitoxantrone-selected cells were enriched for CSCs expressing stem cell markers ALDH, c-kit, Oct-4, and ABCG2, and efficient at forming mammospheres. Tranilast markedly inhibited mammosphere formation by D-CSCs and dissociated formedmammospheres,atpharmacologicallyrelevantconcentrations.ItwaseffectiveagainstD-CSCsofbothHER-2+and triple-negative cell lines. Tranilast was also effective in vivo, since it prevented lung metastasis in mice injected i.v. with triple-negative(MDA-MB-231)mitoxantrone-selectedcells.Themoleculartargetsoftranilastincancerhavebeenunknown, butherewedemonstrateitisanarylhydrocarbonreceptor(AHR)agonistandthisplaysakeyrole.AHRisatranscription factor activated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polycyclic aromatic hydrocarbons and other ligands. TranilastinducedtranslocationoftheAHRtothenucleusandstimulatedCYP1A1expression(amarkerofAHRactivation).It inhibitedbindingoftheAHRto