Lysyl oxidase-like 2 (LOXL2), a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas.
Bottom Line: 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.
Affiliation: Departamento de Bioqu√≠mica, UAM, Instituto de Investigaciones Biom√©dicas "Alberto Sols", CSIC-UAM, IdiPAZ, Instituto de Investigaci√≥n Sanitaria La Paz, Madrid, Spain. email@example.comShow MeSH
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Mentions: To identify the molecular signature associated to highly aggressive breast tumours an expression profile analysis was performed in a sample of 58 grade 3 infiltrative ductal carcinomas (IDC). After processing the arrays data, unsupervised hierarchical clustering sub-classified the samples into two clusters. The main cluster included 43 tumours that express ESR and PR receptors, some luminal markers and/or Her2neu indicating that this cluster included the luminal and Her2neu tumours and was defined as a non-basal breast carcinoma cluster (Supporting Information Fig S1A). The second cluster contained 15 tumours lacking expression of hormone receptors and the Her2neu oncogene, thus representing the basal-like tumours (Supporting Information Fig S1A). A supervised analysis identified a set of 311 genes able to classify the non-basal and basal-like tumours with a FDR <0.2 (Fig 1A). Around 23% of the genes represent genes previously characterized by their expression in luminal and basal/mesenchymal breast cancer cells (Charafe-Jauffret et al, 2006; Neve et al, 2006) (Fig 1B; Supporting Information Table S1). The basal-like tumours showed very low levels of ESR, PR and Her2neu transcripts as compared to the mean values obtained for the non-basal tumours (Fig 1C), indicating that the basal-like cluster indeed contains the triple negative tumours. In addition, the basal-like tumours showed upregulated expression of typical basal genes, like cytokeratins 5/6 (Fig 1C) as well as caveolin1 and p63 (Fig 1B; Supporting Information Table S1). To evaluate the biological relevance of the identified ‚Äúbasal-like breast signature‚ÄĚ (BBS), we tested for its presence in several public breast cancer databases and found that it defines the basal-like tumours in the van 't Veer et al (2002) and Wang et al (2005) series, as well as basal breast cell lines in the Charafe-Jauffret et al (2006) series (Supporting Information Fig S1B).
Affiliation: Departamento de Bioqu√≠mica, UAM, Instituto de Investigaciones Biom√©dicas "Alberto Sols", CSIC-UAM, IdiPAZ, Instituto de Investigaci√≥n Sanitaria La Paz, Madrid, Spain. firstname.lastname@example.org