Browsing by Subject "Targeting lysyl oxidase (LOX)"

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    Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer
    (Nature Research, 2020) Saatçi, Ö.; Kaymak, A.; Raza, Umar; Ersan, Pelin G.; Akbulut, Özge; Banister, C. E.; Sikirzhytski, V.; Tokat, Ünal Metin; Aykut, Gamze; Ansari, 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, Özgür
    Chemoresistance 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.