期刊
BREAST CANCER RESEARCH
卷 11, 期 3, 页码 -出版社
BMC
DOI: 10.1186/bcr2321
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资金
- NIH/NCI [5SC1CA138658-01]
- NIH/UAB Breast SPORE Career Development Award [BC 504370]
- Susan G. Komen Foundation for the Cure
- Cancer Research and Prevention Foundation
- Georgia Cancer Coalition Distinguished Cancer Scholar Award [CIG-07-114]
- Consortium for Industrial Collaboration in Contraceptive Research (CICCR)
- Contraceptive Research and Development Program (CONRAD)
- Eastern Virginia Medical School
- NIH/HD [41749]
- Morehouse School of Medicine Dean's Fund for Minority Student Training [NIH RR03034, 1C06 RR18386]
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [U54HD041749] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [SC1CA138658] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [C06RR018386] Funding Source: NIH RePORTER
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.
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