Abstract 1715: Leptin regulates the IL-1 system in breast cancer

Abstract Leptin and IL-1 are inflammatory cytokines promoting breast cancer angiogenesis that are often linked to worse prognosis. We hypothesize the leptin angiogenic effects in mammary tumor (MT) may be linked to, or regulated, in part by IL-1 signaling, therefore, leptin and IL-1 may have synergistic functions in MT progression. To test this hypothesis leptin-dose (0-6.2 nM) and time-course (0-48h) effects on levels of IL-1 system components (IL-1α, IL-1β, IL-1Ra and IL-1R tI) were investigated in mouse MT-4T1 cells. To determine the contribution of specific leptin-activated signaling pathways on IL-1 regulation several kinase inhibitors AG490 (JAK2/STAT3), PD98059 (MEK/MAPK/ERK1/2), Wortmannin (PI-3K/AKT1), Rapamycin (mToR), Go6976 (PKC-Ca dependent), SB203580 (p38 MAP kinase) and SP600125 (JNK) were used and IL-1 system component levels were determined by ELISA and Western blot. To determine if leptin could regulate its own receptor (long isoform, OB-Rb and all isoforms) flow cytometry was used. Our results show that basal levels of IL-1α were 14 fold higher than IL-1β. Remarkably, leptin up-regulates all IL-1 system components and all OB-R isoforms showing the highest effects at 1.2nM/24h. JAK2/STAT3 and MAPK/ERK 1/2 were essential for leptin upregulation of IL-1 system. In contrast, PI-3K/AKT1, PKC and p38 kinases were mainly linked to leptin regulation of IL-1 receptor-related proteins (IL-1R tI and IL-1Ra). JNK and mTOR were related to leptin-mediated induction of IL-1R tI but were not involved on IL-1α or IL-1Ra regulation. Interestingly, leptin-mediated activation of mTOR appears to be a negative regulator of IL-1α but acts as an inductor of IL-1Ra. In conclusion, leptin is an important regulator of IL-1 system in MT. In turn, IL-1 signaling can promote VEGF expression and tumor macrophage recruitment that could indirectly enhance leptin-mediated angiogenic effects and MT growth. This work was supported in part by NIH/NCI 1SC1CA138658-02; NIH/UAB Breast SPORE Career Development Award; BC 504370 Susan G. Komen Foundation for the Cure and the Georgia Cancer Coalition Distinguished Cancer Scholar Award (to RRGP). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1715.