Breast　cancer　is　the　most　prevalent　malignancy　in　women,　which　remains　untreatable　once　metastatic.　The　treatment　of　advanced　breast　cancer　is　restricted　due　to　chemotherapy　resistance.　We　previously　investigated　anti-cancer　potential　of　a　tumor　selective　oncolytic　adenovirus　along　with　cisplatin　in　three　lung　cancer　cells;　A549,　H292,　and　H661,　and　found　it　very　efficient.　To　our　surprise,　this　virotherapy　showed　remarkable　cytotoxicity　to　chemo-resistant　cancer　cells.　Here,　we　extended　our　investigation　by　using　two　breast　cancer　cells　and　their　resistant　sublines　to　further　validate　CRAd＇s　anti-resistance　properties.　Results　of　in　vitro　and　in　vivo　analyses　recapitulated　the　similar　anti-tumor　potential　of　CRAd.　Based　on　the　molecular　analysis　through　qPCR　and　western　blotting,　we　suggest　upregulation　of　coxsackievirus-adenovirus　receptor　(CAR)　as　a　selective　vulnerability　of　chemotherapy-resistant　tumors.　CAR　knockdown　and　overexpression　experiments　established　its　important　involvement　in　the　success　of　CRAd-induced　tumor　inhibition.　Additionally,　through　transwell　migration　assay　we　demonstrate　that　CRAd　might　have　anti-metastatic　properties.　Mechanistic　analysis　show　that　CRAd　pre-treatment　could　reverse　epithelial　to　mesenchymal　transition　in　breast　cancer　cells,　which　needs　further　verification.　These　insights　may　prove　to　be　a　timely　opportunity　for　the　application　of　CRAd　in　recurrent　drug-resistant　cancers.