LOX-1: a Novel Metabolic Target in Human Breast Cancer

Targeting the metabolic pathways of cancer is a hot topic for drug discovery. OLR1 gene, encodes the cell membrane receptor LOX-1 (Lectin-like oxidized low density lipoprotein receptor). We recently identifies two novel alternative Olr1 isoforms, whose expression is modulated in mouse during developmental stages of cardiogenesis. Hormones such as estrogens and growth factors in the tumor microenvironment contribute to the transcriptional regulation of metabolic gene LOX-1 also through the activation of downstream signaling and a cross-talk among diverse transduction pathways. Our aim is to delineate the role of the metabolic gene codify LOX-1 in breast cancer . A strong up-regulation of LOX-1 was observed in about 70% of breast cancer tissues positively correlated to the tumor stage and grade. Interestingly, LOX-1 expression in tumoral tissues was related to TGFβ expression in the microenvironment. On the contrary a faint LOX-1expression was observed in the normal counterpart of the same patients. A peculiar and atypical nuclear localization was noted only in highly aggressive tumors correlated to HER2 amplification. A positive correlation between the metabolic oncogene FASN and LOX-1 was found in tumors HER2 positive suggestinga direct cross talk among EGFR, FASN and LOX. OLR1 Knock down by shRNAi in MCF7( ER+) and SKBR3 (Her2+) breast cancer cells results in down-regulation of genes necessary for oncogenic transformation and maintenance of transformed phenotypeThe overexpression of LOX-1 specific isoforms in vitro strongly increase MCF12 normal cell proliferation,in cancer cells markedly enhanced proliferation, migration, affecting the epigenetic regulation of cancer pro-survival, and tumor invasion pathways.Altogether, these results suggest that LOX-1 may acts as a molecular link among metabolism, inflammation and cancer, indicating its potential role as biomarker and new molecular target, representing an attractive and concrete opportunity to improve current strategies for breast cancer therapy