Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer
Makaleler > Tam Makale · 2020
Yazarlar: Ozge Saatci, Ayşegül KAYMAK ÖZDEMİR, Umar Raza, Pelin G. Ersan, Ozge Akbulut, Carolyn E. Banister, Vitali Sikirzhytski, Unal Metin Tokat, Gamze Aykut, Suhail A. Ansari, Hayriye Tatli Dogan, Mehmet Dogan, Pouria Jandaghi, Aynur Isik, Fatma Gundogdu, Kemal Kosemehmetoglu, Omer Dizdar, Sercan Aksoy, Aytekin Akyol, Aysegul Uner, Phillip J. Buckhaults, Yasser Riazalhosseini, Ozgur Sahin
NATURE COMMUNICATIONS, SCI Expanded İndekslerine Giren Dergi, Uluslararası, 2020, cilt 11
DOI: 10.1038/s41467-020-16199-4
Özet
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-1 alpha /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. The development of chemoresistance is a major hurdle in triple negative breast cancer (TNBC). Here, the authors show that lysyl oxidase (LOX) is overexpressed in chemoresistant TNBCs, and when inhibited reduces collagen cross-linking, fibronectin fibril assembly, and downstream integrin signalling, overcoming resistance.