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

Ozge Saatci, Aysegul Kaymak, 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 and Ozgur Sahin ()
Additional contact information
Ozge Saatci: University of South Carolina
Aysegul Kaymak: University of South Carolina
Umar Raza: Bilkent University
Pelin G. Ersan: Bilkent University
Ozge Akbulut: Bilkent University
Carolyn E. Banister: University of South Carolina
Vitali Sikirzhytski: University of South Carolina
Unal Metin Tokat: Bilkent University
Gamze Aykut: Bilkent University
Suhail A. Ansari: Bilkent University
Hayriye Tatli Dogan: Ankara Yildirim Beyazit University
Mehmet Dogan: Ankara Oncology Education and Research Hospital
Pouria Jandaghi: McGill University
Aynur Isik: Hacettepe University Transgenic Animal Technologies Research and Application Center
Fatma Gundogdu: Hacettepe University
Kemal Kosemehmetoglu: Hacettepe University
Omer Dizdar: Hacettepe University Cancer Institute
Sercan Aksoy: Hacettepe University Cancer Institute
Aytekin Akyol: Hacettepe University Transgenic Animal Technologies Research and Application Center
Aysegul Uner: Hacettepe University
Phillip J. Buckhaults: University of South Carolina
Yasser Riazalhosseini: McGill University
Ozgur Sahin: University of South Carolina

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-16199-4

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