Leptin Induces Breast Cancer Metastasis Through A Neuropilin-1 (Nrp-1)/Obr Complex

Several studies have demonstrated Neuropilin-1 (NRP-1) implication in tumor progression independently of its known co-receptors. On the basis of growing connections between breast cancer and obesity, we postulated that leptin and its receptor OBR could be potential candidates. First, using NRP-1 over-expression in NRP-1 negative T47D or NRP-1 silencing in NRP-1 positive MDA-MB231 xenografts, we demonstrated that leptin induced metastasis in lymph node only in NRP-1 positive cells. Second, we demonstrated by co-immunoprecipitation, Proximity Ligation assay (duolink) and BRET analysis that NRP-1 is a co-receptor of OBR. Upon leptin exposure this complex is internalized to the nucleus. At this level, NRP-1 Chip-Seq analysis generated from MDA-MB-231 led to identify sequences of RNA polymerase II (Pol2) and transcription factor binding sites of genes implicated in breast cancer metastasis. This finding was confirmed by the detection of NRP-1/Pol2 interaction and by transcriptome analysis of RNA extracts from T47D-NRP-1 xenografts that shows modulation of these genes. In conclusion, we have demonstrated that NRP-1 is a co-receptor of OBR and upon leptin exposure may play a role as a transcription factor regulating genes involved in cancer progression. Thus, NRP-1 might be a therapeutic target to prevent cancer metastasis induced by leptin Citation Format: Zakia Belaid-Choucair, Julie Dam, Nicolas Goudin, Odile Filhole, Claude Cochet, Yves lepelletier, Tereza Coman, Genevieve Courtois, Alain Colige, Marie-Paule Defresne, Ralf Jockers, Olivier Hermine. Leptin induces breast cancer metastasis through a Neuropilin-1 (NRP-1)/OBR complex. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3293. doi:10.1158/1538-7445.AM2014-3293