Leptin decreases susceptibility BC cells to NK-lysis via PGC-1α pathway.

: Large prospective studies established a link between obesity and breast cancer (BC) development. Yet, the mechanisms underlying this association are not fully understood. Among the diverse adipocytokine secreted by hypertrophic adipose tissue, leptin is emerging as a key candidate molecule linking obesity and cancer, since it promotes proliferation and invasiveness of tumors. However, the potential implication of leptin on tumor escape mechanisms remains unknown. This study aims to explore the effect of leptin on tumor resistance to NK lysis and the underlying mechanism. We found that leptin promotes both BC resistance to NK92-mediated lysis and β oxidation on MCF-7, by the up-regulation of a master regulator of mitochondrial biogenesis, peroxisome proliferator activated receptor coactivator-1 α (PGC-1α). Using adenoviral approaches, we show that acute elevation of PGC-1α enhances the fatty acid oxidation pathway and decreases the susceptibility of BC cells to NK92-mediated lysis. Importantly, we identified new regulatory functions of PGC-1α and leptin in regulating the expression of hypoxia-inducible factor-1 alpha (HIF-1α by tumor cells, a transcriptional factor with pleiotropic role in cancer. We further demonstrate that basal BC cells MDA-MB-231 and BT-20 exhibit an increased PGC-1α mRNA level, an enhanced activity of oxidative phosphorylation and are more resistance to NK92 lysis in comparison with luminal BC cells (MCF7 and MDA-361). Altogether, our results demonstrate for the first time how leptin could promote tumor resistance to immune attacks. Reagents blocking leptin or PGC-1α activity might aid in developing new therapeutic strategies to limit tumor development in obese BC patients.