Leptin-signaling inhibition results in efficient anti-tumor activity in estrogen receptor positive or negative breast cancer

INTRODUCTION: We have shown previously that treatment with pegylated leptin peptide receptor antagonist 2 (PEG-LPrA2) reduced the expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor type 2 (VEGFR2) and growth of 4T1-breast cancer (BC) in syngeneic mice. In this investigation, PEG-LPrA2 was used to evaluate whether the inhibition of leptin signaling has differential impact on the expression of pro-angiogenic and pro-proliferative molecules and growth of human estrogen receptor-positive (ER(+)) and estrogen receptor-negative (ER(-)) BC xenografts hosted by immunodeficient mice. METHODS: To test the contribution of leptin signaling to BC growth and expression of leptin-targeted molecules, PEG-LPrA2 treatment was applied to severe immunodeficient mice hosting established ER(+ )(MCF-7 cells; ovariectomized/supplemented with estradiol) and ER(- )(MDA-MB231 cells) BC xenografts. To further assess leptin and PEG-LPrA2 effects on ER(+ )and ER(- )BC, the expression of VEGF and VEGFR2 (protein and mRNA) was investigated in cell cultures. RESULTS: PEG-LPrA2 more effectively reduced the growth of ER(+ )(>40-fold) than ER(- )BC (twofold) and expression of pro-angiogenic (VEGF/VEGFR2, leptin/leptin receptor OB-R, and IL-1 receptor type I) and pro-proliferative molecules (proliferating cell nuclear antigen and cyclin D(1)) in ER(+ )than in ER(- )BC. Mouse tumor stroma in ER(+ )BC expressed high levels of VEGF and leptin that was induced by leptin signaling. Leptin upregulated the transcriptional expression of VEGF/VEGFR2 in MCF-7 and MDA-MB231 cells. CONCLUSIONS: These results suggest that leptin signaling plays an important role in the growth of both ER(+ )and ER(- )BC that is associated with the leptin regulation of pro-angiogenic and pro-proliferative molecules. These data provide support for the potential use of leptin-signaling inhibition as a novel treatment for ER(+ )and ER(- )BC.