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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

Abstract

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.

References

  1. Ahima, R. S. and Flier, J. S. (2000). Adipose tissue as an endocrine organ. Trends Endocrinol. Metab. 11, 327-332. https://doi.org/10.1016/S1043-2760(00)00301-5
  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. https://doi.org/10.1096/fj.00-0162
  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. https://doi.org/10.1074/jbc.275.19.14563
  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. https://doi.org/10.1073/pnas.93.16.8374
  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. https://doi.org/10.1074/jbc.272.51.32686
  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. https://doi.org/10.1016/S1097-2765(00)80062-3
  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. https://doi.org/10.1074/jbc.274.42.30059
  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. https://doi.org/10.1074/jbc.M007439200
  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 https://doi.org/10.1210/jc.82.9.2904
  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. https://doi.org/10.1093/aje/kwg236
  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. https://doi.org/10.1161/01.RES.83.10.1059
  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. https://doi.org/10.1677/jme.0.0260145
  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. https://doi.org/10.1073/pnas.101564798
  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. https://doi.org/10.1210/jc.83.6.2149
  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. https://doi.org/10.1093/molehr/6.10.951
  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. https://doi.org/10.1016/S0015-0282(98)00187-3
  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. https://doi.org/10.1074/jbc.M301695200
  19. Chlebowski, R. T., Aiello, E. and McTiernan, A. (2002). Weight loss in breast cancer patient management. J. Clin. Oncol. 20, 1128-1143. https://doi.org/10.1200/JCO.20.4.1128
  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. https://doi.org/10.1210/jc.2004-0297
  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. https://doi.org/10.1038/nm0596-585
  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. https://doi.org/10.1002/jcb.21911
  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. https://doi.org/10.3181/00379727-216-44153B
  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. https://doi.org/10.1023/A:1021891825399
  25. Cohen, B., Novick, D. and Rubinstein, M. (1996). Modulation of insulin activities by leptin. Science 274, 1185-1188. https://doi.org/10.1126/science.274.5290.1185
  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. https://doi.org/10.2337/diabetes.44.12.1467
  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. https://doi.org/10.1210/jc.82.10.3230
  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. https://doi.org/10.1074/jbc.272.29.18304
  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. https://doi.org/10.1074/jbc.270.27.15958
  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. https://doi.org/10.1016/S0006-291X(02)00205-X
  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. https://doi.org/10.1016/j.febslet.2004.03.089
  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. https://doi.org/10.1210/jc.82.10.3267
  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. https://doi.org/10.1186/1471-2407-8-305
  38. Folkman, J. (1995). Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1, 27-31. https://doi.org/10.1038/nm0195-27
  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. https://doi.org/10.1124/mol.53.2.234
  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. https://doi.org/10.1016/j.amjsurg.2004.07.031
  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. https://doi.org/10.1073/pnas.93.25.14564
  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. https://doi.org/10.1158/1078-0432.CCR-04-0203
  43. Garofalo, C. and Surmacz, E. (2006). Lepin and cancer. J. Cell Physiol. 207, 12-22. https://doi.org/10.1002/jcp.20472
  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. https://doi.org/10.1158/1078-0432.CCR-05-1913
  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. https://doi.org/10.1073/pnas.93.13.6231
  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. https://doi.org/10.1055/s-2007-978726
  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. https://doi.org/10.1074/jbc.M601991200
  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. https://doi.org/10.1385/ENDO:26:1:019
  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. https://doi.org/10.1053/gast.2001.25490
  50. Harvie, M., Hooper, L. and Howell, A. H. (2003). Central obesity and breast cancer risk: A systematic review. Obes. Rev. 4, 157-173. https://doi.org/10.1046/j.1467-789X.2003.00108.x
  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. https://doi.org/10.1210/en.141.6.1955
  52. Hino, M., Nakao, T., Yamane, T., Ohta, K., Takubo, T. and Tatsumi, N. (2000). Leptin receptor and leukemia. Leuk. Lymphoma 36, 457-461. https://doi.org/10.3109/10428190009148392
  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. https://doi.org/10.1093/jnci/94.22.1704
  54. Huang, L., Wang, Z. and Li, C. (2001). Modulation of circulating leptin levels by its soluble receptor. J. Biol. Chem. 276, 6343-6349. https://doi.org/10.1074/jbc.M009795200
  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. https://doi.org/10.1093/oxfordjournals.aje.a010265
  56. Hynes, G. R. and Jones, P. J. (2001). Leptin and its role in lipid metabolism. Curr. Opin. Lipidol. 12, 321-327. https://doi.org/10.1097/00041433-200106000-00012
  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. https://doi.org/10.1158/1078-0432.CCR-03-0749
  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. https://doi.org/10.1006/bbrc.1997.7399
  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. https://doi.org/10.3322/canjclin.57.1.43
  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. https://doi.org/10.1016/j.bbrc.2007.04.004
  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. https://doi.org/10.1210/jc.82.8.2510
  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. https://doi.org/10.1172/JCI119818
  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. https://doi.org/10.1177/002215540205000204
  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. https://doi.org/10.1016/S0303-7207(01)00678-5
  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. https://doi.org/10.1074/jbc.271.5.2365
  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. https://doi.org/10.1385/ENDO:18:2:179
  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. https://doi.org/10.1007/s10585-008-9231-x
  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. https://doi.org/10.1136/gut.47.4.481
  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. https://doi.org/10.1152/ajpendo.00003.2004
  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. https://doi.org/10.1200/JCO.2009.22.4436
  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. https://doi.org/10.1016/S0014-5793(97)00013-6
  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. https://doi.org/10.1023/A:1015770423167
  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. https://doi.org/10.2174/1389450053765879
  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. https://doi.org/10.1002/jcp.20588
  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. https://doi.org/10.1016/j.gene.2005.10.018
  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. https://doi.org/10.1006/bbrc.1999.0843
  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. https://doi.org/10.1210/en.2006-0224
  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. https://doi.org/10.1016/S0167-4889(02)00276-8
  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. https://doi.org/10.1210/en.142.11.4827
  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. https://doi.org/10.1074/jbc.M304984200
  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. https://doi.org/10.1038/emm.2001.17
  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. https://doi.org/10.1023/A:1008903727238
  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. https://doi.org/10.1111/j.1467-789X.2004.00142.x
  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. https://doi.org/10.1074/jbc.M312999200
  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. https://doi.org/10.1038/370061a0
  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. https://doi.org/10.1158/0008-5472.CAN-08-1952
  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. https://doi.org/10.1093/ajcn/69.4.584
  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. https://doi.org/10.1158/0008-5472.CAN-05-0598
  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. https://doi.org/10.1126/science.281.5383.1683
  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. https://doi.org/10.1210/jc.83.5.1810
  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. https://doi.org/10.1016/j.jss.2007.10.012
  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. https://doi.org/10.1016/S0022-4804(03)00166-5
  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. https://doi.org/10.1016/j.jss.2004.01.017
  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. https://doi.org/10.1126/science.7871433
  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. https://doi.org/10.1210/jc.86.3.1341
  102. Stephenson, G. D. and Rose, D. P. (2003). Breast cancer and obesity: An update. Nutr. Cancer 45, 1-16. https://doi.org/10.1207/S15327914NC4501_1
  103. Stetler-Stevenson, W. G. (1990). Type IV collagenase in tumor invasion and metastasis. Cancer Metastasis Rev. 9, 289- 303. https://doi.org/10.1007/BF00049520
  104. Surmacz, E. (2007). Obesity hormone leptin: A new target in breast cancer? Breast Cancer Res. 9, 301. https://doi.org/10.1186/bcr1638
  105. Sweeney, G. (2002). Leptin signaling. Cell Signal 14, 655-663. https://doi.org/10.1016/S0898-6568(02)00006-2
  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. https://doi.org/10.1073/pnas.050580497
  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. https://doi.org/10.1073/pnas.94.8.3801
  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. https://doi.org/10.1016/0092-8674(95)90151-5
  109. Tartaglia, L. A. (1997). The leptin receptor. J. Biol. Chem. 272, 6093-6096. https://doi.org/10.1074/jbc.272.10.6093
  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. https://doi.org/10.1007/BF01833261
  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. https://doi.org/10.1016/S0014-2999(98)00884-X
  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. https://doi.org/10.1677/ERC-06-0068
  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. https://doi.org/10.1016/S1359-6101(96)00040-8
  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. https://doi.org/10.1074/jbc.272.7.4065
  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. https://doi.org/10.1002/(SICI)1097-4644(19990501)73:2<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. https://doi.org/10.1158/0008-5472.CAN-04-0655
  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. https://doi.org/10.1016/S0014-5793(03)00440-X
  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. https://doi.org/10.1016/S0303-7207(99)00194-X
  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. https://doi.org/10.1038/372425a0
  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. https://doi.org/10.1172/JCI3920