Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer

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buir.contributor.authorRaza, Umar
buir.contributor.authorErsan, Pelin G.
buir.contributor.authorAkbulut, Özge
buir.contributor.authorTokat, Ünal Metin
buir.contributor.authorAykut, Gamze
buir.contributor.authorAnsari, Suhail A.
buir.contributor.authorŞahin, Özgür
dc.citation.epage17en_US
dc.citation.issueNumber1en_US
dc.citation.spage1en_US
dc.citation.volumeNumber11en_US
dc.contributor.authorSaatçi, Ö.
dc.contributor.authorKaymak, A.
dc.contributor.authorRaza, Umar
dc.contributor.authorErsan, Pelin G.
dc.contributor.authorAkbulut, Özge
dc.contributor.authorBanister, C. E.
dc.contributor.authorSikirzhytski, V.
dc.contributor.authorTokat, Ünal Metin
dc.contributor.authorAykut, Gamze
dc.contributor.authorAnsari, Suhail A.
dc.contributor.authorTatlı-Doğan, H.
dc.contributor.authorDoğan, M.
dc.contributor.authorJandaghi, P.
dc.contributor.authorIşık, A.
dc.contributor.authorGündoğdu, F.
dc.contributor.authorKösemehmetoğlu, K.
dc.contributor.authorDizdar, Ö.
dc.contributor.authorAksoy, S.
dc.contributor.authorAkyol, A.
dc.contributor.authorÜner, A.
dc.contributor.authorBuckhaults, P. J.
dc.contributor.authorRiazalhosseini, Y.
dc.contributor.authorŞahin, Özgür
dc.date.accessioned2021-03-01T11:51:14Z
dc.date.available2021-03-01T11:51:14Z
dc.date.issued2020
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractChemoresistance 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.en_US
dc.identifier.doi10.1038/s41467-020-16199-4en_US
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/11693/75670
dc.language.isoEnglishen_US
dc.publisherNature Researchen_US
dc.relation.isversionofhttps://dx.doi.org/10.1038/s41467-020-16199-4en_US
dc.source.titleNature Communicationsen_US
dc.subjectTargeting lysyl oxidase (LOX)en_US
dc.subjectTriple negative breast cancer (TNBC)en_US
dc.subjectRNA-sequencingen_US
dc.titleTargeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast canceren_US
dc.typeArticleen_US

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