Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer
In: Nature Communications, Jg. 11 (2020), Heft 1, S. 1-17
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Zugriff:
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.
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.
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Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer
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Autor/in / Beteiligte Person: | Pelin Gülizar Ersan ; Gundogdu, Fatma ; Uner, Aysegul ; Sikirzhytski, Vitali ; Unal Metin Tokat ; Kaymak, Aysegul ; Buckhaults, Phillip ; Hayriye Tatlı Doğan ; Aykut, Gamze ; Banister, Carolyn E. ; Kosemehmetoglu, Kemal ; Dizdar, Omer ; Ansari, Suhail A. ; Raza, Umar ; Dogan, Mehmet ; Saatci, Ozge ; Sahin, Ozgur ; Isik, Aynur ; Akbulut, Ozge ; Aksoy, Sercan ; Akyol, Aytekin ; Riazalhosseini, Yasser ; Jandaghi, Pouria ; Ersan, Pelin G. ; Akbulut, Özge ; Tokat, Ünal Metin ; Şahin, Özgür |
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Zeitschrift: | Nature Communications, Jg. 11 (2020), Heft 1, S. 1-17 |
Veröffentlichung: | Nature Portfolio, 2020 |
Medientyp: | unknown |
ISSN: | 2041-1723 (print) |
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