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.
Highlights
Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype
In 77 TNBC patients treated with chemotherapy, we showed that higher lysyl oxidase (LOX) protein levels were significantly associated with worse disease-free survival (DFS) (p-value = 0.019, Fig. 2q)
We identified a mechanism of chemotherapy resistance that involves activation of the HIF1A/miR142-3p/LOX/integrin alpha 5 (ITGA5)/FN1 axis in TNBCs
Summary
Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. 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. There is still a dire need to identify novel molecular targets to improve the therapeutic benefit of chemotherapy given in first-line settings, as well as in patients with advanced, chemotherapy resistant TNBC. This will have immediate translational impact on improving the pCR rate to standard chemotherapy and will improve patient outcome for the mostaggressive breast cancer subtype
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