Saatçi, Ö.Kaymak, A.Raza, UmarErsan, Pelin G.Akbulut, ÖzgeBanister, C. E.Sikirzhytski, V.Tokat, Ünal MetinAykut, GamzeAnsari, Suhail A.Tatlı-Doğan, H.Doğan, M.Jandaghi, P.Işık, A.Gündoğdu, F.Kösemehmetoğlu, K.Dizdar, Ö.Aksoy, S.Akyol, A.Üner, A.Buckhaults, P. J.Riazalhosseini, Y.Şahin, Özgür2021-03-012021-03-0120202041-1723http://hdl.handle.net/11693/75670Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxia-repressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients.EnglishTargeting lysyl oxidase (LOX)Triple negative breast cancer (TNBC)RNA-sequencingArticle10.1038/s41467-020-16199-4