Abstract #4704: Differential effects of leptin-peptide receptor antagonist (LPrA) on breast cancer estrogen receptor positive and negative

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO The incidence of breast cancer (BC) is directly correlated to obesity and leptin levels in post-menopausal women, but the specific contributions of leptin to the pathology of BC is still unknown. It is hypothesized that leptin signaling mediates the regulation of molecules involved in the onset and/or growth of BC. Our previous data show that the inhibition of leptin signaling with a specific leptin peptide receptor antagonist (LPrA2) delayed the onset and reduced the growth of mouse 4T1 derived BC in syngeneic mice. To test this hypothesis in human BC, immunodeficient mice hosting either MCF-7 (estrogen receptor positive, ER+) or MDA-MB231 (estrogen receptor negative, ER-) BC xenografts were treated with pegylated-LPrA2 (PEG-LPrA2; half-life 63h) or scrambled peptide as control (Sc-PEG) before or after the orthotopical inoculation of cancer cells. MCF-7 cells were inoculated into ovariectomized mice implanted with an E2 capsule. To test the biologic, LPrA2, in preventing BC establishment and/or growth, mice were implanted with PEG-LPrA2 or Sc-PEG capsules and i.v. treated with these compounds every 48h one week before cell inoculation. Capsules containing PEG-peptides and E2 were replaced every 21 days. To further investigate the impact of PEG-LPrA2 on the growth of BC, mice hosting established BC were i.v. injected every 48h with PEG-LPrA2 or Sc-PEG. Pre- and post-tumor development treatments ended after 8 and 4 weeks, respectively. PEG-LPrA2 treatment to mice hosting MCF-7 derived BC significantly delayed the onset (30 days) and reduced the growth of tumors (>40 fold; p<0.05, one-way ANOVA test). In comparison, MDA-MB231 derived BC showed delayed onset (5 days) and tumor growth reduction (2 fold) to a lesser extent. No differences in body and carcass weights or food intake were found between mice treated with PEG-LPrA2 or Sc-PEG. Treatment with PEG-LPrA2 significantly reduced the levels of VEGF/VEGFR2, leptin, leptin receptor (OB-R), CD68, PCNA, and cyclin D1 in both BC types. In vitro studies using immunoprecipitation/Western blot and Real-Time RT-PCR revealed that leptin signaling is linked to the transcriptional regulation of VEGF/VEGFR2 in both, MCF-7 and MDA-MB231 cells. However, leptin-mediated effects on VEGF/VEGFR2 expression were more significant in MCF-7 than in MDA-MB231 cell cultures. In conclusion, these data reinforce the idea that either in BC ER+ or ER- leptin signaling plays an important role in the regulation of angiogenesis, inflammation, and proliferation-related molecules which in turn could positively contribute to the growth of BC. However, BC ER + were more sensitive to the effects of leptin signaling inhibition. Present data support the potential use of PEG-LPrA2 for leptin-signaling inhibition as a novel adjuvant therapy for BC. This could be of particular interest for that population at greatest risk, i.e., post-menopausal and obese women. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4704.