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Gonzalez, RR, Cherfils, S, Escobar, M, Yoo, JH, Carino, C, Styer, AK, Sullivan, BT, Sakamoto, H, Olawaiye, A, Serikawa, T, Lynch, MP and Rueda, BR (2006) Leptin signaling promotes the growth of mammary tumors and increases the expression of vascular endothelial growth factor (VEGF) and its receptor type two (VEGF-R2). J. Biol. Chem. 281:26320-8
To gain insight into the mechanism(s) by which leptin contributes to mammary tumor (MT) development we investigated the effects of leptin, kinase inhibitors, and/or leptin receptor antagonists (LPrA2) on 4T1 mouse mammary cancer cells in vitro and LPrA2 on 4T1-MT development in vivo. Leptin increases the expression of vascular endothelial growth factor (VEGF), its receptor (VEGF-R2), and cyclin D1 through phosphoinositide 3-kinase, Janus kinase 2/signal transducer and activator of transcription 3, and/or extracellular signal-activated kinase 1/2 signaling pathways. In contrast to leptin-induced levels of cyclin D1 the changes in VEGF or VEGF-R2 were more dependent on specific signaling pathways. Incubation of 4T1 cells with anti-VEGF-R2 antibody increased leptin-mediated VEGF expression suggesting an autocrine/paracrine loop. Pretreatment of syngeneic mice with LPrA2 prior to inoculation with 4T1 cells delayed the development and slowed the growth of MT (up to 90%) compared with controls. Serum VEGF levels and VEGF/VEGF-R2 expression in MT were significantly lower in mice treated with LPrA2. Interestingly, LPrA2-induced effects were more pronounced in vivo than in vitro suggesting paracrine actions in stromal, endothelial, and/or inflammatory cells that may impact the growth of MT. Although all the mechanism(s) by which leptin contributes to tumor development are unknown, it appears leptin stimulates an increase in cell numbers, and the expression of VEGF/VEGF-R2. Together, these results provide further evidence suggesting leptin is a MT growth-promoting factor. The inhibition of leptin signaling could serve as a potential adjuvant therapy for treatment of breast cancer and/or provide a new target for the designing strategies to prevent MT development.
Animals; Cell Line, Tumor; Cyclin D1/metabolism; Female; Humans; Leptin/genetics; Leptin/metabolism; Mammary Neoplasms, Animal/metabolism; Mice; Mice, Inbred BALB C; Peptides/genetics; Peptides/metabolism; Protein Isoforms/genetics; Protein Isoforms/metabolism; RNA, Small Interfering/genetics; RNA, Small Interfering/metabolism; Receptors, Cell Surface/antagonists & inhibitors; Receptors, Cell Surface/genetics; Receptors, Cell Surface/metabolism; Receptors, Leptin; Signal Transduction/physiology; Vascular Endothelial Growth Factor A/genetics; Vascular Endothelial Growth Factor A/metabolism; Vascular Endothelial Growth Factor Receptor-2/genetics; Vascular Endothelial Growth Factor Receptor-2/metabolism