Lysyl oxidase‐like 2 (LOXL2), a new regulator of cell polarity required for metastatic dissemination of basal‐like breast carcinomas

Basal‐like breast carcinoma is characterized by the expression of basal/myoepithelial markers, undifferentiated phenotype, highly aggressive behaviour and frequent triple negative status (ESR−, PR−, Her2neu−). We have previously shown that epithelial–mesenchymal transition (EMT) occurs in basal‐like breast tumours and identified Lysyl‐oxidase‐like 2 (LOXL2) as an EMT player and poor prognosis marker in squamous cell carcinomas. We now show that LOXL2 mRNA is overexpressed in basal‐like human breast carcinomas. Breast carcinoma cell lines with basal‐like phenotype show a specific cytoplasmic/perinuclear LOXL2 expression, and this subcellular distribution is significantly associated with distant metastatic incidence in basal‐like breast carcinomas. LOXL2 silencing in basal‐like carcinoma cells induces a mesenchymal‐epithelial transition (MET) associated with a decrease of tumourigenicity and suppression of metastatic potential. Mechanistic studies indicate that LOXL2 maintains the mesenchymal phenotype of basal‐like carcinoma cells by a novel mechanism involving transcriptional downregulation of Lgl2 and claudin1 and disorganization of cell polarity and tight junction complexes. Therefore, intracellular LOXL2 is a new candidate marker of basal‐like carcinomas and a target to block metastatic dissemination of this aggressive breast tumour subtype.