Leptin-signaling inhibition results in efficient anti-tumor activity in estrogen receptor positive or negative breast cancer
1 Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310, USA
2 Vincent Center for Reproductive Biology, Massachusetts General Hospital, 55 Fruit Street Their 901, Boston, MA 02114, USA
3 Boston Biomedical Research Institute, 64 Grove Street, Watertown, MA 02472, USA
4 Department of Pathology, Microbiology and Immunology, University of South Carolina, School of Medicine, 6311 Garners Ferry Road, Columbia, SC 29208, USA
5 Department of Physiology, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310, USA
6 Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, 55 Fruit Street, Boston, MA 02115, USA
7 Department of Surgery, Division of Surgical Oncology; Microbiology, Immunology, and Molecular Genetics, Jonnson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, 650 Charles Young Drive South, Los Angeles, CA 90095, USA
Breast Cancer Research 2009, 11:R36 doi:10.1186/bcr2321Published: 16 June 2009
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.
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.
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 D1) 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.
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.