Roles of Leptin in Cancer Progression

  • Kang, Yu-Jin (College of Pharmacy, Duksung Women's University) ;
  • Moon, A-Ree (College of Pharmacy, Duksung Women's University)
  • Received : 2010.09.27
  • Accepted : 2010.10.13
  • Published : 2010.10.31


Growing evidence suggests a prominent role for leptin in human cancer progression. The intricate pattern of leptin cross-talk with other associated signaling pathways is a critical area of research that will ultimately contribute to comprehending the role of leptin in cancer progression. This review summarizes a portion of the current understanding of leptin signaling, with a critical focus on its contribution to tumor cell invasion and metastasis. Five topics are addressed in this review: (1) Leptin receptor, (2) Leptin signaling, (3) Leptin and cancer, and (4) Leptin and tumor invasion. Due to the complex cellular effects of leptin, a more precise understanding of leptin signaling pathways must still be elucidated. Leptin is clearly a major factor for stimulating tumor progression through a complex spectrum of interplay and cross-talk among various signaling molecules. An understanding of the role of leptin in invasion and metastasis will provide valuable information for establishing strategies to modulate leptin signaling, which should be a high priority for the development of anti-cancer therapeutics.


  1. Ahima, R. S. and Flier, J. S. (2000). Adipose tissue as an endocrine organ. Trends Endocrinol. Metab. 11, 327-332.
  2. Attoub, S., Noe, V., Pirola, L., Bruyneel, E., Chastre, E., Mareel, M., Wymann, M. P. and Gespach, C. (2000). Leptin promotes invasiveness of kidney and colonic epithelial cells via phosphoinositide 3-kinase-, Rho-, and Rac-dependent signaling pathways. FASEB J. 14, 2329-2338.
  3. Banks, A. S., Davis, S. M., Bates, S. H. and Myers, M. G. (2000). Activation of downstream signals by the long form of the leptin receptor. J. Biol. Chem. 275, 14563-14572.
  4. Bauer, K. R., Brown, M., Cress, R. D., Parise, C. A. and Caggiano, V. (2007). Descriptive analysis of estrogen receptor (ER)‐negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triplenegative phenotype. Am. Can. Soc. 109, 1721-1728.
  5. Baumann, H., Morella, K. K., White, D. W., Dembski, M., Bailon, P. S., Kim, H., Lai, C. F. and Tartaglia, L. A. (1996). The fulllength leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proc. Natl. Acad. Sci. USA. 93, 8374-8378.
  6. Bjorbaek, C., Uotani, S., da Silva, B. and Flier, J. S. (1997). Divergent signaling capacities of the long and short isoforms of the leptin recptor. J. Biol. Chem. 272, 32686-32695.
  7. Bjorbaek, C., Elmquist, J. K., Frantz, J. D., Shoelson, S. E. and Flier, J. S. (1998). Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol. Cell 1, 619-625.
  8. Bjorbaek, C., El-Haschimi, K., Frantz, J. D. and Flier, J. S. (1999). The role of SOCS-3 in leptin signaling and leptin resistance. J. Biol. Chem. 274, 30059-30065.
  9. Bjorbaek, C., Buchholz, R. M., Davis, S. M., Bates, S. H., Pierroz, D. D., Gu, H., Neel, B. G., Myers, M. G. and Flier, J. S. Jr. (2001). Divergent roles of SHP-2 in ERK activation by leptin receptors. J. Biol. Chem. 276, 4747-4755.
  10. Blum, W. F., Englaro, P., Hanitsch, S., Juul, A., Hertel, N. T., Muller, J., Skakkebaek, N. E., Heiman, M. L., Birkett, M., Attanasio, A. M., Kiess, W. and Rascher, W. (1997). Plasma leptin levels in healthy children and adolescents: Dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone. J. Clin. Endocrinol. Metab. 82, 2904-2910
  11. Borugian, M. J., Sheps, S. B., Kim-Sing, C., Olivotto, I. A., Van Patten, C., Dunn, B. P., Coldman, A. J., Potter, J. D., Gallagher, R. P. and Hislop, T. G. (2003). Waist-to-hip ratio and breast cancer mortality. Am. J. Epidemiol. 158, 963-968.
  12. Bouloumie, A., Drexler, H. C., Lafontan, M. and Busse, R. (1998). Leptin, the product of Ob gene, promotes angiogenesis. Circ. Res. 83, 1059-1066.
  13. Briscoe, C. P., Hanif, S., Arch, J. R. and Tadayyon, M. (2001). Fatty acids inhibit leptin signalling in BRIN-BD11 insulinoma cells. J. Mol. Endocrinol. 26, 145-154.
  14. Cao, R., Brakenhielm, E., Wahlestedt, C., Thyberg, J. and Cao, Y. (2001). Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc. Natl. Acad. Sci. USA. 98, 6390-6395.
  15. Casabiell, S., Pineiro, V., Peino, R., Lage, M., Camina, J., Gallego, R., Vallego, L. G., Dieguez, C. and Casanueva, F. F. (1998). Gender differences in both spontaneous and stimulated leptin secretion by human omental adipose tissue in vitro: Dexamethasone and estradiol stimulate leptin release in women, but not in men. J. Clin. Endocrinol. Metab. 83, 2149-2155.
  16. Castellucci, M., Matteis, R., De Meisser, A., Cancello, R., Monsurro, V., Islami, D., Sarzani, R., Marzioni, D., Cinti, S. and Bischof, P. (2000). Leptin modulates extracellular matrix molecules and metalloproteinases: possible implications for trophoblast invasion. Mol. Hum. Reprod. 6, 951-958.
  17. Castracane, V. D., Kraemer, R. R., Franken, M. A., Kraemer, G. R. and Gimpel, T. (1998). Serum leptin concentration in women: Effect of age, obesity, and estrogen administration. Fertil. Steril. 70, 472-477.
  18. Catalano, S., Marsico, S., Giordano, C., Mauro, L., Rizza, P., Panno, M. L. and Ando, S. (2003). Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line. J. Biol. Chem. 278, 28668-28676.
  19. Chlebowski, R. T., Aiello, E. and McTiernan, A. (2002). Weight loss in breast cancer patient management. J. Clin. Oncol. 20, 1128-1143.
  20. Choi, J. H., Park, S. H., Leung, P. C. and Choi, K. C. (2004). Expression of leptin receptors and potential effects of leptin on the cell growth and activation of mitogen-activated protein kinases in ovarian cancer cells. J. Clin. Endocrinol. Metab. 90, 207-210.
  21. Cioffi, J. A., Shafer, A. W., Zupancic, T. J., Smith-Gbur, J., Mikhail, A., Platika, D. and Snodgrass, H. R. (1996). Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction. Nat. Med. 2, 585-589.
  22. Cirillo, D., Rachiglio, A. M., La Montagna, R., Giordano, A. and Normanno, N. (2008). Leptin signaling in breast cancer: an overview. J. Cell. Biochem. 105, 956-964.
  23. Cleary, M. P. and Maihle, N. J. (1997). The role of body mass index in the relative risk of developing premenopausal versus postmenopausal breast cancer. Proc. Soc. Exp. Biol. Med. 216, 28-43.
  24. Cleary, M. P., Phillips, F. C., Getzin, S. C., Jacobson, T. L., Jacobson, M. K., Christensen, T. A., Juneja, S. C., Grande, J. P. and Maihle, N. J. (2003). Genetically obese MMTVTGF- alpha/Lep(ob)Lep(ob) female mice do not develop mammary tumors. Breast Cancer Res. Treat. 77, 205-215.
  25. Cohen, B., Novick, D. and Rubinstein, M. (1996). Modulation of insulin activities by leptin. Science 274, 1185-1188.
  26. Cusin, I., Sainsbury, A., Doyle, P., Rohner-Jeanrenaud, F. and Jeanrenaud, B. (1995). The ob gene and insulin. A relationship leading to clues to the understanding of obesity. Diabetes 44, 1467-1470.
  27. Dagogo-Jack, S., Selke, G., Melson, A. K. and Newcomer, J. W. (1997). Robust leptin secretory responses to dexamethasone in obese subjects. J. Clin. Endocrinol. Metab. 82, 3230-3233.
  28. Devos, R., Guisez, Y., Van der Heyden, J., White, D. W., Kalai, M., Fountoulakis, M. and Plaetinck, G. (1997). Ligandindependent dimerization of the extracellular domain of the leptin receptor and determination of the stoichiometry of leptin binding. J. Biol. Chem. 272, 18304-18310.
  29. De Vos, P., Saladin, R., Auwerx, J. and Staels, B. (1995). Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake. J. Biol. Chem. 270, 15958-15961.
  30. Dieudonne, M. N., Machinal-Quelin, F., Serazin-Leroy, V., Leneveu, M. C., Pecquery, R. and Giudicelli, Y. (2002). Leptin mediates a proliferative response in human MCF7 breast cancer cells. Biochem. Biophys. Res. Commun. 293, 622-628.
  31. Eisemberg, A., Biener, E., Charlier, M., Krishnan, R. V., Dijane, J., Herman, B. and Gertler, A. (2004). Transactivation of erbB2 by short and long isoforms of leptin receptors. FEBS Lett. 565, 139-142.
  32. Elbers, J. M., Asscheman, H., Seidell, J. C., Frolich, M., Meinders, A. E. and Gooren, L. J. (1997). Reversal of the sex difference in serum leptin levels upon cross-sex hormone administration in transsexuals. J. Clin. Endocrinol. Metab. 82, 3267-3270.
  33. Ellis, L. M. and Fidler, I. J. (1996) Angiogenesis and metastasis. Eur. J. Cancer 32A, 2451-2460.
  34. Enger, S. M., Ross, R. K., Paganini-Hill, A., Carpenter, C. L. and Bernstein, L. (2000). Body size, physical activity, and breast cancer hormone receptor status: Results from two casecontrol studies. Cancer Epidemiol. Biomarkers. Prev. 9, 681-687.
  35. Fain, J. N., Leffler, C. W. and Bahouth, S. W. (2000). Eicosanoids as endogenous regulators of leptin release and lipolysis by mouse adipose tissue in primary culture. J. Lipid. Res. 41, 1689-1694.
  36. Fidler, I. J. (1990). Critical factors in the biology of human cancer metastasis. Cancer Res. 50, 6130-6138.
  37. Fiorio, A., Mercanti, A., Terrasi, M., Micciolo, R., Remo, A., Auriemma, A., Molino, A., Parolin, V., Di Stefano, B., Bonetti, F., Giordano, A., Cetto, G. L. and Surmacz, E. (2008). Leptin/HER2 crosstalk in breast cancer: in vitro study and preliminary in vivo anlysis. BMC Cancer 8, 305-315.
  38. Folkman, J. (1995). Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1, 27-31.
  39. Fong, T. M., Huang, R. R., Tota, M. R., Mao, C., Smith, T., Varnerin, J., Karpitskiy, V. V., Krause, J. E. and Van der Ploeg, L. H. (1998). Localization of leptin binding domain in the leptin receptor. Mol. Pharmacol. 53, 234-240.
  40. Frankenberry, K. A., Somasundar, P., McFadden, D. W. and Vona-Davis, L. C. (2004). Leptin induces cell migration and the expression of growth factors in human prostate cancer cells. Am. J. Surg. 188, 560-565.
  41. Gainsford, T., Wilson, T. A., Metcalf, D., Handman, E., McFarlane, C., Ng, A., Alexander, W. S. and Hilton, D. J. (1996). Leptin can induce proliferation, differentiation, functional activation of hemopoietic cells. Proc. Natl. Acad. Sci. USA. 93, 14564-14568.
  42. Garofalo, C., Sisci, D. and Surmacz, E. (2004). Leptin interferes with the effects of the antiestrogen ICI 182,780 in MCF-7 breast cancer cells. Clin. Cancer Res. 10, 6466-6475.
  43. Garofalo, C. and Surmacz, E. (2006). Lepin and cancer. J. Cell Physiol. 207, 12-22.
  44. Garofalo, C., Koda, M., Cascio, S., Sulkowska, M., Kanczuga- Koda, L., Golaszewska, J., Russo, A., Sulkowski, S. and Surmacz, E. (2006). Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: Possible role of obesity-related stimuli. Clin. Cancer Res. 12, 1447-1453.
  45. Ghilardi, N., Ziegler, S., Wiestner, A., Stoffel, R., Heim, M. H. and Skoda, R. C. (1996). Defective STAT signaling by the leptin receptor in diabetic mice. Proc. Natl. Acad. Sci. USA. 93, 6231-6235.
  46. Glasow, A., Bornstein, S. R, Chrousos, G. P., Brown, J. W and Scherbaum, W. A. (1999). Detection of Ob-receptor in human adrenal neoplasms and effect of leptin on adrenal cell proliferation. Horm. Metab. Res. 31, 247-251.
  47. Gonzalez, R. R., Cherfils, S., Escobar, M., Yoo, J. H., Carino, C., Styer, A. K., Sullivan, B. T., Sakamoto, H., Olawaiye, A., Serikawa, T., Lynch, M. P. and Rueda, B. R. (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, 26320-26328.
  48. Han, C., Zhang, H. T., Du, L., Liu, X., Jing, J., Zhao, X., Yang, X. and Tian, B. (2005). Serum levels of leptin, insulin, and lipids in relation to breast cancer in China. Endocrine 26, 19-24.
  49. Hardwick, J. C., Van Den Brink, G. R., Offerhaus, G. J., Van Deventer, S. J. and Peppelenbosch, M. P. (2001). Leptin is a growth factor for colonic epithelial cells. Gastroenterology 121, 79-90.
  50. Harvie, M., Hooper, L. and Howell, A. H. (2003). Central obesity and breast cancer risk: A systematic review. Obes. Rev. 4, 157-173.
  51. Hileman, S. M., Tornoe, J., Flier, J. S. and Bjorbaek, C. (2000). Transcellular transport of leptin by the short leptin receptor isoform ObRa in madin-darby canine kidney cells. Endocrinology 141, 1955-1966.
  52. Hino, M., Nakao, T., Yamane, T., Ohta, K., Takubo, T. and Tatsumi, N. (2000). Leptin receptor and leukemia. Leuk. Lymphoma 36, 457-461.
  53. Hu, X., Juneja, S. C., Maihle, N. J. and Cleary, M. P. (2002). Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor a in MCF-7 cells. J. Natl. Cancer. Inst. 94, 1704-1711.
  54. Huang, L., Wang, Z. and Li, C. (2001). Modulation of circulating leptin levels by its soluble receptor. J. Biol. Chem. 276, 6343-6349.
  55. Huang, W. Y., Newman, B., Millikan, R. C., Schell, M. J., Hulka, B. S. and Moorman, P. G. (2000). Hormone-related factors and risk of breast cancer in relation to estrogen receptor and progesterone receptor status. Am. J. Epidemiol. 151, 703- 714.
  56. Hynes, G. R. and Jones, P. J. (2001). Leptin and its role in lipid metabolism. Curr. Opin. Lipidol. 12, 321-327.
  57. Ishikawa, M., Kitayama, J. and Nagawa, H. (2004). Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin. Cancer Res. 10, 4325-4331.
  58. Islam, M. S., Morton, N. M., Hansson, A. and Emilsson, V. (1997). Rat insulinoma-derived pancreatic beta-cells express a functional leptin receptor that mediates a proliferative response. Biochem. Biophys. Res. Commun. 238, 851-855.
  59. Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J. and Thun, M. J. (2007). Cancer Statistics, 2007. CA Cancer J. Clin. 57, 43-66.
  60. Jiang, H., Yu, J., Guo, H., Song, H. and Chen, S. (2007). Upregulation of survivin by leptin/STAT3 signaling in MCF-7 cells. Biochem. Biophys. Res. Commun. 368, 1-5.
  61. Jockenhovel, F., Blum, W. F., Vogel, E., Englaro, P., Muller- Wieland, D., Reinwein, D., Rascher, W. and Krone, W. (1997). Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men. J. Clin. Endocrinol. Metab. 82, 2510-2513.
  62. Kulkarni, R. N., Wang, Z. L., Wang, R. M., Hurley, J. D., Smith, D. M., Ghatei, M. A., Withers, D. J., Gardiner, J. V., Bailey, C. J. and Bloom, S. R. (1997). Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice. J. Clin. Invest. 100, 2729-2736.
  63. Kume, K., Satomura, K., Nishisho, S., Kitaoka, E., Yamanouchi, K., Tobiume, S. and Nagayama, M. (2002). Potential role of leptin in endochondral ossification. J. Histochem. Cytochem. 50, 159-169.
  64. Laud, K., Gourdou, I., Pessemesse, L., Peyrat, J. P. and Djiane, J. (2002). Identification of leptin receptors in human breast cancer: Functional activity in the T47-D breast cancer cell line. Mol. Cell Endocrinol. 188, 219-226.
  65. Leroy, P., Dessolin, S., Villageois, P., Moon, B. C., Friedman, J. M., Ailhaud, G. and Dani, C. (1996). Expression of ob gene in adipose cells. Regulation by insulin. J. Biol. Chem. 271, 2365-2368.
  66. Liotta, L. A. and Stetler-Stevenson, W. G. (1991). Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Res. 51, 5054-5059
  67. Liu, Z., Uesaka, T., Watanabe, H. and Kato, N. (2001). High fat diet enhances colonic cell proliferation and carcinogenesis in rats by elevating serum leptin. Int. J. Oncol. 19, 1009-1014.
  68. Ma, C., Lin, H., Leonard, S. S., Shi, X., Ye, J. and Luo, J. (2003). Overexpression of ErbB2 enhances ethanol-stimulated intracellular signaling and invasion of human mammary epithelial and breast cancer cells in vitro. Oncogene 14, 5281-5290.
  69. Machinal-Quelin, F., Dieudonne, M. N., Pecquery, R., Leneveu, M. C. and Giudicelli, Y. (2002). Direct in vitro effects of androgens and estrogens on ob gene expression and leptin secretion in human adipose tissue. Endocrine 18, 179-184.
  70. McMurtry, V., Simeone, A. M., Nieves-Alicea, R. and Tari, A. M. (2009). Leptin utilizes Jun- N-terminal kinases to stimulate the invasion of MCF-7 breast cancer cells. Clin. Exp. Metastasis 26, 197-204.
  71. Mix, H., Widjaja, A., Jandl, O., Cornberg, M., Kaul, A., Goke, M., Beil, W., Kuske, M., Brabant, G., Manns, M. P. and Wagner, S. (2000). Expression of leptin and leptin receptor isoforms in the human stomach. Gut 47, 481-486.
  72. Miyazawa-Hoshimoto, S., Takahashi, K., Bujo, H., Hashimoto, N., Yagui, K. and Saito, Y. (2004). The roles of degree of fat deposition and its localization on VEGF expression in adipocytes. Am. J. Physiol. Endocrinol. Metab. 288, 1128- 1136.
  73. Moon, H. G., Han, W. and Noh, D. Y. (2009). Underweight and breast cancer recurrence and death: a report from the Korean breast cancer society. J. Clin. Oncol. 27, 5899-5905.
  74. Nakashima, K., Narazaki, M. and Taga, T. (1997). Leptin receptor (OB-R) oligomerizes with itself but not with its closely related cytokine signal transducer gp130. FEBS Lett. 403, 79-82.
  75. Neville, M. C., McFadden, T. B. and Forsyth, I. (2002). Hormonal regulation of mammary differentiation and milk secretion. J. Mammary. Gland Biol. Neoplasia. 7, 49-66.
  76. Normanno, N., Bianco, C., Strizzi, L., Mancino, M., Maiello, M. R., De Luca, A., Caponigro, F. and Salomon, D. S. (2005). The ErbB receptors and their ligands in cancer: An overview. Curr. Drug Targets 6, 243-257.
  77. Normanno, N., De Luca, A., Maiello, M. R., Campiglio, M., Napolitano, M., Mancino, M., Carotenuto, A., Viglietto, G. and Menard, S. (2006a). The MEK/MAPK pathway is involved in the resistance of breast cancer cells to the EGFR tyrosine kinase inhibitor gefitinib. J. Cell Physiol. 207, 420-427.
  78. Normanno, N., De Luca, A., Bianco, C., Strizzi, L., Mancino, M., Maiello, M. R., Carotenuto, A., De Feo, G., Caponigro, T. and Salomons, D. S. (2006b). Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366, 2-16.
  79. O’Brien, S. N., Welter, B. H. and Price, T. M. (1999). Presence of leptin in breast cell lines and breast tumors. Biochem. Biophys. Res. Commun. 259, 695-698.
  80. Ogunwobi, O., Mutungi, G. and Beales, I. L. (2006). Leptin stimulates proliferation and inhibits apoptosis in Barrett’s esophageal adenocarcinoma cells by cyclooxygenase-2- dependent, prostaglandin-E2-mediated transactivation of the epidermal growth factor receptor and c-Jun NH2-terminal kinase activation. Endocrinology 147, 4505.
  81. Okumura, M., Yamamoto, M., Sakuma, H., Kojima, T., Maruyama, T., Jamali, M., Cooper, D. R. and Yasuda, K. (2002). Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: Reciprocal involvement of PKC-alpha and PPAR expression. Biochim. Biophys. Acta. 1592, 107-116.
  82. Okuya, S., Tanabe, K., Tanizawa, Y. and Oka, Y. (2001). Leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis. Endocrinology 142, 4827-4830.
  83. Onuma, M., Bub, J. D., Rummel, T. L. and Iwamoto, Y. (2003). Prostate cancer cell-adipocyte interaction: Leptin mediates androgen-independent prostate cancer cell proliferation through c-Jun NH2-terminal kinase. J. Biol. Chem. 278, 42660-42667.
  84. Park, H. Y., Kwon, H. M., Lim, H. J., Hong, B. K., Lee, J. Y., Park, B. E., Jang, Y., Cho, S. Y. and Kim, H. S. (2001). Potential role of leptin in angiogenesis: Leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro. Exp. Mol. Med. 33, 95-102.
  85. Petridou, E., Papadiamantis, Y., Markopoulos, C., Spanos, E., Dessypris, N. and Trichopoulos, D. (2000). Leptin and insulin growth factor I in relation to breast cancer (Greece). Cancer Causes Control 11, 383-388.
  86. Potter, J. D., Cerhan, J. R., Sellers, T. A., McGovern, P. G., Drinkard, C., Kushi, L. R. and Folsom, A. R. (1995). Progesterone and estrogen receptors and mammary neoplasia in the Iowa Women’s Health Study: How many kinds of breast cancer are there? Cancer Epidemiol. Biomarkers Prev. 4, 319-326.
  87. Rose, D. P., Gilhooly, E. M. and Nixon, D. W. (2002). Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin (review). Int. J. Oncol. 21, 1285- 1292.
  88. Rose D. P., Komninou, D. and Stephenson, G. D. (2004). Obesity, adipocytokines, and insulin resistance in breast cancer. Obese. Rev. 5, 153-165.
  89. Rouet-Benzineb, P., Aparicio, T., Guilmeau, S., Pouzet, C., Descatoire, V., Buyse, M. and Bado, A. (2004). Leptin counteracts sodium butyrate-induced apoptosis in human colon cancer HT-29 cells via NF-kappaB signaling. J. Biol. Chem. 279, 16495-16502.
  90. Sato, H., Takino, T., Okada, Y., Cao, J., Shinagawa, A. and Yamamoto, E. (1994). A matrix metalloproteinase expressed on the surface of invasive tumor cells. Nature 370, 61-65.
  91. Saxena, N. K., Taliaferro-Smith, L., Knight, B. B., Merlin, D., Anania, F. A., O’Regan, R. M. and Sharma, D. (2008). Bidirectional crosstalk between leptin and insulin-like growth factor-I signaling promotes invasion and migration of breast cancer cells via transactivation of epidermal growth factor receptor. Cancer Res. 68, 9712-9722.
  92. Schwartz, M. W., Baskin, D. G., Kaiyala, K. J. and Woods, S. C. (1999). Model for the regulation of energy balance and adiposity by the central nervous system 1-3. Am. J. Clin. Nutr. 69, 584-596.
  93. Shida, D., Kitayama, J. and Mori, K. (2005). Transactivation of epidermal growth factor receptor is involved in leptin-induced activation of janus-activated kinase 2 and extracellular signal-regulated kinase 1/2 in human gastric cancer cells. Cancer Res. 65, 9159.
  94. Sierra-Honigmann, M. R., Nath, A. K., Murakami, C., Garcia- Cardena, G., Papapetropoulos, A., Sessa, W. C., Madge, L. A., Schechner, J. S., Schwabb, M. B., Polverini, P. J. and Flores-Riveros, J. R. (1998). Biological action of leptin as an angiogenic factor. Science 281, 1683-1686.
  95. Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A. and McGuire, W. L. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 235177-235182.
  96. Smith-Kirwin, S. M., O’Connor, D. M., De Johnston, J., Lancey, E. D., Hassink, S. G. and Funanage, V. L. (1998). Leptin expression in human mammary epithelial cells and breast milk. J. Clin. Endocrinol. Metab. 83, 1810-1813.
  97. Soma, D., Kitayama, Joji., Yamashita, H., Miyato, H., Ishikawa, M. and Nagawa, H. (2008). Leptin augments proliferation of breast cancer cells via transactivation of HER2. J. Surg. Res. 149, 9-14.
  98. Somasundar, P., Yu, A. K., Vona-Davis, L. and McFadden, D. W. (2003). Differential effects of leptin on cancer in vitro. J. Surg. Res. 113, 50-55.
  99. Somasundar, P., Frankenberry, K. A., Skinner, H., Vedula, G., McFadden, D. W., Riggs, D., Jackson, B., Vangilder, R., Hileman, S. M. and Vona-Davis, L. C. (2004). Prostate cancer cell proliferation is influenced by leptin. J. Surg. Res. 118, 71-82.
  100. Stahl, N., Farruggella, T. J., Boulton, T. G., Zhong, Z., Darnell, J. E. and Yancopoulos, G. D. (1995). Choice of STATs and other substrates specified by modular tyrosine based motifs in cytokine receptors. Science 267, 1349-1353.
  101. Stattin, P., Soderberg, S., Hallmans, G., Bylund, A., Kaaks, R., Stenman, U. H., Bergh, A. and Olsson, T. (2001). Leptin is associated with increased prostate cancer risk: A nested case-referent study. J. Clin. Endocrinol. Metab. 86, 1341- 1345.
  102. Stephenson, G. D. and Rose, D. P. (2003). Breast cancer and obesity: An update. Nutr. Cancer 45, 1-16.
  103. Stetler-Stevenson, W. G. (1990). Type IV collagenase in tumor invasion and metastasis. Cancer Metastasis Rev. 9, 289- 303.
  104. Surmacz, E. (2007). Obesity hormone leptin: A new target in breast cancer? Breast Cancer Res. 9, 301.
  105. Sweeney, G. (2002). Leptin signaling. Cell Signal 14, 655-663.
  106. Szanto, I. and Kahn, C. R. (2000). Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. Proc. Natl. Acad. Sci. USA. 97, 2355-2360.
  107. Takeda, K., Naguchi, K, Shi, W., Tanaka, T., Matsumoto, M., Yoshida, N., Kishimoto, T. and Akira, S. (1997). Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl. Acad. Sci. USA. 94, 3801-3804.
  108. Tartaglia, L. A., Dembski, M., Weng, X., Deng, N., Culpepper, J., Devos, R., Richards, G. J., Campfield, L. A., Clark, F. T., Deeds, J., Muir, C., Sanker, S., Moriarty, A., Moore, K. J., Smutko, J. S., Mays, G. G., Woolf, E. A., Monroe, C. A. and Tepper, R. I. (1995). Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263-1271.
  109. Tartaglia, L. A. (1997). The leptin receptor. J. Biol. Chem. 272, 6093-6096.
  110. Tessitore, L., Vizio, B., Jenkins, O., De Stefano, I., Ritossa, C., Argiles, J. M., Benedetto, C. and Mussa, A. (2000). Leptin expression in colorectal and breast cancer patients. Int. J. Mol. Med. 5, 421-426.
  111. Tryggvason, K., Hoyhtya, M. and Pyke, C. (1993). Type IV collagenase in invasive tumors. Breast Cancer Res. Treat 24, 209-218.
  112. Tsuchiya, T., Shimizu, H., Horie, T. and Mori, M. (1999). Expression of leptin receptor in lung: Leptin as a growth factor. Eur. J. Pharmacol. 365, 273-279.
  113. Ura, H., Bonfil, R. D., Reich, R., Reddel, R., Pfeifer, A., Harris, C. C. and Klein-Sznto, A. J. (1989). Expression of type IV collagenase and procollagen genes and its correlation with the tumorigenic, invasive, and metastatic abilities of oncogenetransformed human bronchial epithelial cells. Cancer Res. 49, 4615-4621.
  114. Vona-Davis, L. and Rose, D. P. (2007). Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr. Relat. Cancer 14, 189-206.
  115. White, D. W. and Tartaglia, L. A. (1996). Leptin and OB-R: Body weight regulation by a cytokine receptor. Cytokine Growth Factor Rev. 7, 303-309.
  116. White, D. W., Kuropatwinski, K. K., Devos, R., Baumann, H. and Tartaglia, L. A. (1997). Leptin receptor (OB-R) signaling. J. Biol. Chem. 272, 4065-4071.
  117. White, D. W. and Tartaglia, L. A. (1999). Evidence for ligandindependent homooligomerization of leptin receptor (OB-R) isoforms: A proposed mechanism permitting productive long-form signaling in the presence of excess shortform expression. J. Cell. Biochem. 73, 278-288.<278::AID-JCB13>3.0.CO;2-W
  118. Yarden, Y. (2001). Biology of HER2 and its importance in breast cancer. Oncology 61, 1-13.
  119. Yin, N., Wang, D., Zhang, H., Yi, X., Sun, X., Shi, B., Wu, H., Wu, G., Wang, X. and Shang, Y. (2004). Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin. Cancer Res. 64, 5870-5875.
  120. Zabeau, L., Lavens, D., Peelman, F., Eycherman, S., Vandekerckhove, J. and Tavernier, J. (2003). The ins and outs of leptin receptor activation. FEBS Lett. 546, 45-50.
  121. Zhang, H. H., Kumar, S., Barnett, A. H. and Eggo, M. C. (2000). Tumor necrosis factor-alpha exerts dual effects on human adipose leptin synthesis and release. Mol. Cell. Endocrinol. 159, 79-88.
  122. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L. and Friedman, J. M. (1994). Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425-432.
  123. Zhao, A. Z., Bornfeldt, K. E. and Beavo, J. A. (1998). Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. J. Clin. Invest. 102, 869-873.