The identification of new predictive biomarkers and therapeutic target for tailored therapy in breast cancer onset and progression is an interesting challenge. OLR-1 gene encodes the cell membrane receptor LOX-1 (lectin-like oxidized low-density lipoprotein receptor). We have recently identified a novel alternative OLR-1 isoform, LOX-1Δ4, whose expression and functions are still not clarified. In the present paper, we demonstrated that LOX-1 is overexpressed in 70% of human breast cancer (n = 47) and positively correlated to the tumor stage and grade (p < 0.01). Observations on LOX-1 and its splice variant Δ4 pointed out a different expression pattern correlated to breast cancer phenotypes. Overexpressing LOX-1 and LOX-1Δ4 in vitro, we obtained a strong enhancement of proliferative rate and a downregulation of cell death-related proteins. In addition, we observed a strong modulation of histone H4 acetylation and Ku70, the limiting factor of DNA double-strand breaks repair machinery implied in apoptosis inhibition and drug resistance acquisition. Moreover, LOX-1Δ4 overexpression is able to increase proliferation in a non-tumorigenic epithelial cell line, MCF12-F, acting as an oncogene. 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 tailored therapy.