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J. Biol. Chem., Vol. 281, Issue 36, 26320-26328, September 8, 2006

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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)^*

Ruben R. Gonzalez¹, Salandre Cherfils, Maria Escobar, Jin H. Yoo, Cecilia Carino, Aaron K. Styer^¶, Brian T. Sullivan, Hideo Sakamoto^¶, Alex Olawaiye^¶, Takehiro Serikawa^¶, Maureen P. Lynch^¶, and Bo R. Rueda^¶2

From the Boston Biomedical Research Institute, Watertown, Massachusetts 02472, the Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, and the ^¶Harvard Medical School, Boston, Massachusetts 02115

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.

Received for publication, March 2, 2006 , and in revised form, June 28, 2006.

^* This work was supported in part by Susan G. Komen Foundation for Breast Cancer Grant BC 504370 (to R. R. G.), the Cancer Research and Prevention Foundation (to R. R. G.), Consortium for Industrial Collaboration in Contraceptive Research (CICCR), a program of Contraceptive Research and Development Program (CONRAD), Eastern Virginia Medical School Grant CIG-02-87 (to R. R. G.), Advanced Medical Research Foundation (to B. R. R.), and Vincent Memorial Hospital Research Funds (to B. R. R. and A. K. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Morehouse School of Medicine, 720 Westview Dr., Atlanta, GA 30310. Tel.: 404-752-1581; E-mail: rgonzalez{at}msm.edu. ² To whom correspondence may be addressed: Vincent Center for Reproductive Biology, MA General Hospital, THR901A, 55 Fruit St., Boston, MA 02114. Tel.: 617-724-2825; E-mail: brueda{at}partners.org.

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