Email updates

Keep up to date with the latest news and content from Breast Cancer Research and BioMed Central.

Open Access Highly Accessed Research article

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

Ruben Rene Gonzalez123*, Amber Watters1, Yanbo Xu1, Udai P Singh4, David R Mann5, Bo R Rueda26 and Manuel L Penichet7

Author Affiliations

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

For all author emails, please log on.

Breast Cancer Research 2009, 11:R36  doi:10.1186/bcr2321

Published: 16 June 2009

Abstract

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 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.

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.