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

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 hypoxiarepressed 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.

Resistance to Neoadjuvant Treatment in Breast Cancer: Clinicopathological and Molecular Predictors

“…In this regard, a recent study employed several systems that mimic in vivo TN BC chemoresistance, such as xenograft models, three-dimensional cultures, and primary breast cancer organoids, to identify that Lysyl oxidase (LOX) is a key inducer chemoresistance in TN BC. Indeed, higher LOX was associated with shorter survival in chemotherapy-treated TN breast cancer patients’ organoids [ 99 ].…”

Proliferation, migration and invasion of triple negative breast cancer cells are suppressed by berbamine via the PI3K/Akt/MDM2/p53 and PI3K/Akt/mTOR signaling pathways

“…TNBC is the most aggressive subtype of breast cancer and accounts for 15~20% of all breast cancers worldwide ( 34 ). Metastasis is the primary cause of mortality in patients with breast cancer ( 35 ).…”

Targeting Lysyl Oxidase Family Meditated Matrix Cross-Linking as an Anti-Stromal Therapy in Solid Tumours

“…LOX family members are upregulated in a number of different cancer types, and high levels of LOX family expression, as well as elevated deposition of fibrillar collagen in tumours, is associated with poor patient outcomes (see Table 1 and Table 2 ) [ 42 , 43 , 44 , 45 ]. Changes in LOX family member regulation, expression and subsequently enzymatic activity are therefore important factors in cancer progression.…”