Skip to main content

Advertisement

SpringerLink
Log in

Leptin and Adiponectin: Emerging Therapeutic Targets in Breast Cancer

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Obesity is a recognized risk factor for breast cancer development and poorer response to therapy. Two major fat tissue-derived adipokines, leptin and adiponectin have been implicated in mammary carcinogenesis. Leptin appears to promote breast cancer progression through activation of mitogenic, antiapoptotic, and metastatic pathways, while adiponectin may restrict tumorigenic processes primarily by inhibiting cell metabolism. Furthermore, adiponectin is known to counteract detrimental leptin effects in breast cancer models. Thus, therapeutic inhibition of pro-neoplastic leptin pathways and reactivation of anti-neoplastic adiponectin signaling may benefit breast cancer patients, especially the obese subpopulation. This review focuses on current experimental strategies aiming at leptin and adiponectin pathways in breast cancer models. Novel leptin receptor antagonists and adiponectin receptor agonists as well as other compounds for therapeutic modulation of adipokine pathways are discussed in detail, including potential pharmacological advantages and limitations of these approaches.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

aa:

Amino acid

Ab:

Antibody

Aca1:

ObR antagonist, first generation

AdipoR1/2:

Adiponectin receptors 1 and 2

ADP355:

Adiponectin peptidomimetic, AdipoR agonist

AICAR:

5-aminoimidazole carboxamide ribonucleotide

Akt:

Akt kinase

Allo-aca:

ObR antagonist, second generation

AMPK:

Adenosine monophosphate-activated protein kinase

BBB:

Blood-brain barrier

BMI:

Body mass index

CNS:

Central nervous system

COX-2:

Cyclooxygenase 2

D-Ser:

ObR antagonist, peripheral

ERK1/2:

Extracellular-signal-regulated kinases 1 and 2

ERα:

Estrogen receptor α

FGF:

Fibroblast growth factor

gAd:

Globular adiponectin

GLUT1:

Glucose transporter 1

HER2:

Human epidermal growth factor receptor 2

HIF1α:

Hypoxia-inducible factor 1α

IGF-1R:

Insulin-like growth factor 1 receptor

IL1:

Interleukin 1

JAK:

Janus kinase

JNK:

Stress-responsive c-Jun N-terminal kinase

mTOR:

Mammalian target of rapamycin

NF-κB:

Nuclear factor-κB

ob :

Obesity gene

ObR:

Leptin receptor

ObRb:

Leptin receptor, long form

PA:

Pomolic acid

PgR:

Progesterone receptor

PI-3K:

Phosphoinositide 3 kinase

PPARα, γ:

Peroxisome proliferator-activated receptor α, γ

PTP1B:

Protein tyrosine phosphatase 1B

siRNA:

Small interfering RNA

SOCS3:

Suppressor of cytokine signaling 3

STAT3:

Signal transducer and activator of transcription 3

TNFα:

Tumor necrosis factor α

TZD:

Thiazolidinedione

VEGF:

Vascular endothelial growth factor

VEGFR2:

VEGF receptor 2

References

  1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425–32.

    PubMed  CAS  Google Scholar 

  2. Zhang F, Basinski MB, Beals JM, Briggs SL, Churgay LM, Clawson DK, et al. Crystal structure of the obese protein leptin-E100. Nature. 1997;387(6629):206–9. doi:10.1038/387206a0.

    PubMed  CAS  Google Scholar 

  3. Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN, et al. The stomach is a source of leptin. Nature. 1998;394(6695):790–3.

    PubMed  CAS  Google Scholar 

  4. Wang J, Liu R, Hawkins M, Barzilai N, Rossetti L. A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature. 1998;393(6686):684–8.

    PubMed  CAS  Google Scholar 

  5. Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, et al. Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med. 1997;3(9):1029–33.

    PubMed  CAS  Google Scholar 

  6. Hu X, Juneja SC, Maihle NJ, Cleary MP. Leptin–a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst. 2002;94(22):1704–11.

    PubMed  CAS  Google Scholar 

  7. Sweeney G. Cardiovascular effects of leptin. Nat Rev Cardiol. 2010;7(1):22–9. doi:10.1038/nrcardio.2009.224.

    PubMed  CAS  Google Scholar 

  8. Wauters M, Considine RV, Van Gaal LF. Human leptin: from an adipocyte hormone to an endocrine mediator. Eur J Endocrinol/Eur Fed Endocr Soc. 2000;143(3):293–311.

    CAS  Google Scholar 

  9. Tartaglia LA. The leptin receptor. J Biol Chem. 1997;272(10):6093–6.

    PubMed  CAS  Google Scholar 

  10. Barr VA, Lane K, Taylor SI. Subcellular localization and internalization of the four human leptin receptor isoforms. J Biol Chem. 1999;274(30):21416–24.

    PubMed  CAS  Google Scholar 

  11. Lollmann B, Gruninger S, Stricker-Krongrad A, Chiesi M. Detection and quantification of the leptin receptor splice variants Ob-Ra, b, and, e in different mouse tissues. Biochem Biophys Res Commun. 1997;238(2):648–52. doi:10.1006/bbrc.1997.7205.

    PubMed  CAS  Google Scholar 

  12. Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R, et al. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci U S A. 1997;94(13):7001–5.

    PubMed  CAS  Google Scholar 

  13. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature. 1996;379(6566):632–5.

    PubMed  CAS  Google Scholar 

  14. Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404(6778):661–71. doi:10.1038/35007534.

    PubMed  CAS  Google Scholar 

  15. Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C, et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron. 1999;23(4):775–86.

    PubMed  CAS  Google Scholar 

  16. Liuzzi A, Savia G, Tagliaferri M, Lucantoni R, Berselli ME, Petroni ML, et al. Serum leptin concentration in moderate and severe obesity: relationship with clinical, anthropometric and metabolic factors. Int J Obes Relat Metab Disord : J Int Assoc Study Obes. 1999;23(10):1066–73.

    CAS  Google Scholar 

  17. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 2000;100(2):197–207.

    PubMed  CAS  Google Scholar 

  18. Morton NM, Emilsson V, de Groot P, Pallett AL, Cawthorne MA. Leptin signalling in pancreatic islets and clonal insulin-secreting cells. J Mol Endocrinol. 1999;22(2):173–84.

    PubMed  CAS  Google Scholar 

  19. Ring BD, Scully S, Davis CR, Baker MB, Cullen MJ, Pelleymounter MA, et al. Systemically and topically administered leptin both accelerate wound healing in diabetic ob/ob mice. Endocrinology. 2000;141(1):446–9.

    PubMed  CAS  Google Scholar 

  20. Siegrist-Kaiser CA, Pauli V, Juge-Aubry CE, Boss O, Pernin A, Chin WW, et al. Direct effects of leptin on brown and white adipose tissue. J Clin Invest. 1997;100(11):2858–64. doi:10.1172/JCI119834.

    PubMed  CAS  Google Scholar 

  21. Kalra SP. Central leptin insufficiency syndrome: an interactive etiology for obesity, metabolic and neural diseases and for designing new therapeutic interventions. Peptides. 2008;29(1):127–38.

    PubMed  CAS  Google Scholar 

  22. Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord : J Int Assoc Study Obes. 2002;26(11):1407–33. doi:10.1038/sj.ijo.0802142.

    CAS  Google Scholar 

  23. Zabeau L, Lavens D, Peelman F, Eyckerman S, Vandekerckhove J, Tavernier J. The ins and outs of leptin receptor activation. FEBS Lett. 2003;546(1):45–50.

    PubMed  CAS  Google Scholar 

  24. Sweeney G. Leptin signalling. Cell Signal. 2002;14(8):655–63.

    PubMed  CAS  Google Scholar 

  25. Jarde T, Perrier S, Vasson MP, Caldefie-Chezet F. Molecular mechanisms of leptin and adiponectin in breast cancer. Eur J Cancer. 2011;47(1):33–43. doi:10.1016/j.ejca.2010.09.005.

    PubMed  CAS  Google Scholar 

  26. Garofalo C, Surmacz E. Leptin and cancer. J Cell Physiol. 2006;207(1):12–22. doi:10.1002/jcp.20472.

    PubMed  CAS  Google Scholar 

  27. Guo S, Liu M, Gonzalez-Perez RR. Role of Notch and its oncogenic signaling crosstalk in breast cancer. Biochim Biophys Acta. 2011;1815(2):197–213. doi:10.1016/j.bbcan.2010.12.002.

    PubMed  CAS  Google Scholar 

  28. Zhou W, Guo S, Gonzalez-Perez RR. Leptin pro-angiogenic signature in breast cancer is linked to IL-1 signalling. Br J Cancer. 2011;104(1):128–37. doi:10.1038/sj.bjc.6606013.

    PubMed  CAS  Google Scholar 

  29. Guo S, Gonzalez-Perez RR. Notch, IL-1 and leptin crosstalk outcome (NILCO) is critical for leptin-induced proliferation, migration and VEGF/VEGFR-2 expression in breast cancer. PloS One. 2011;6(6):e21467. doi:10.1371/journal.pone.0021467.

    PubMed  CAS  Google Scholar 

  30. Beccari S, Kovalszky I, Wade JD, Otvos Jr L, Surmacz E. Designer peptide antagonist of the leptin receptor with peripheral antineoplastic activity. Peptides. 2013;44:127–34. doi:10.1016/j.peptides.2013.03.027.

    PubMed  CAS  Google Scholar 

  31. Mauro L, Catalano S, Bossi G, Pellegrino M, Barone I, Morales S, et al. Evidences that leptin up-regulates E-cadherin expression in breast cancer: effects on tumor growth and progression. Cancer Res. 2007;67(7):3412–21.

    PubMed  CAS  Google Scholar 

  32. Lim CT, Kola B, Korbonits M. AMPK as a mediator of hormonal signalling. J Mol Endocrinol. 2010;44(2):87–97. doi:10.1677/JME-09-0063.

    PubMed  CAS  Google Scholar 

  33. Ferla R, Haspinger E, Surmacz E. Metformin inhibits leptin-induced growth and migration of glioblastoma cells. Oncol Lett. 2012;4(5):1077–81. doi:10.3892/ol.2012.843.

    PubMed  CAS  Google Scholar 

  34. Dzamko NL, Steinberg GR. AMPK-dependent hormonal regulation of whole-body energy metabolism. Acta Physiol (Oxf). 2009;196(1):115–27. doi:10.1111/j.1748-1716.2009.01969.x.

    CAS  Google Scholar 

  35. Perera CN, Chin HG, Duru N, Camarillo IG. Leptin-regulated gene expression in MCF-7 breast cancer cells: mechanistic insights into leptin-regulated mammary tumor growth and progression. J Endocrinol. 2008;199(2):221–33.

    PubMed  CAS  Google Scholar 

  36. Saxena NK, Saliba G, Floyd JJ, Anania FA. Leptin induces increased alpha2(I) collagen gene expression in cultured rat hepatic stellate cells. J Cell Biochem. 2003;89(2):311–20. doi:10.1002/jcb.10494.

    PubMed  CAS  Google Scholar 

  37. Han DC, Isono M, Chen S, Casaretto A, Hong SW, Wolf G, et al. Leptin stimulates type I collagen production in db/db mesangial cells: glucose uptake and TGF-beta type II receptor expression. Kidney Int. 2001;59(4):1315–23. doi:10.1046/j.1523-1755.2001.0590041315.x.

    PubMed  CAS  Google Scholar 

  38. Cheng A, Uetani N, Simoncic PD, Chaubey VP, Lee-Loy A, McGlade CJ, et al. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev Cell. 2002;2(4):497–503.

    PubMed  CAS  Google Scholar 

  39. Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, et al. PTP1B regulates leptin signal transduction in vivo. Dev Cell. 2002;2(4):489–95.

    PubMed  CAS  Google Scholar 

  40. Vona-Davis L, Rose DP. Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer. 2007;14(2):189–206.

    PubMed  CAS  Google Scholar 

  41. Scolaro L, Cassone M, Kolaczynski JW, Jr. Otvos L, Surmacz E. Leptin-based therapeutics. Expert Rev Endocrinol Metab. 2010;5:875–89.

    CAS  Google Scholar 

  42. Surmacz E. Obesity hormone leptin: a new target in breast cancer? Breast Cancer Res. 2007;9(1):301. doi:10.1186/bcr1638.

    PubMed  Google Scholar 

  43. Otvos Jr L, Surmacz E. Targeting the leptin receptor: a potential new mode of treatment for breast cancer. Expert Rev Anticancer Ther. 2011;11(8):1147–50. doi:10.1586/era.11.109.

    PubMed  CAS  Google Scholar 

  44. Fiorio E, Mercanti A, Terrasi M, Micciolo R, Remo A, Auriemma A, et al. Leptin/HER2 crosstalk in breast cancer: in vitro study and preliminary in vivo analysis. BMC Cancer. 2008;8:305.

    PubMed  Google Scholar 

  45. Garofalo C, Koda M, Cascio S, Sulkowska M, Kanczuga-Koda L, Golaszewska J, et al. Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli. Clin Cancer Res Off J Am Assoc Cancer Res. 2006;12(5):1447–53.

    CAS  Google Scholar 

  46. Grossmann ME, Cleary MP. The balance between leptin and adiponectin in the control of carcinogenesis - focus on mammary tumorigenesis. Biochimie. 2012. doi:10.1016/j.biochi.2012.06.013.

    PubMed  Google Scholar 

  47. Miyoshi Y, Funahashi T, Tanaka S, Taguchi T, Tamaki Y, Shimomura I, et al. High expression of leptin receptor mRNA in breast cancer tissue predicts poor prognosis for patients with high, but not low, serum leptin levels. Int J Cancer. 2006;118(6):1414–9.

    PubMed  CAS  Google Scholar 

  48. Otvos Jr L, Kovalszky I, Riolfi M, Ferla R, Olah J, Sztodola A, et al. Efficacy of a leptin receptor antagonist peptide in a mouse model of triple-negative breast cancer. Eur J Cancer. 2011;47(10):1578–84. doi:10.1016/j.ejca.2011.01.018.

    PubMed  CAS  Google Scholar 

  49. Ishikawa M, Kitayama J, Nagawa H. Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2004;10(13):4325–31.

    CAS  Google Scholar 

  50. Zheng Q, Dunlap SM, Zhu J, Downs-Kelly E, Rich J, Hursting SD, et al. Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth in obese mice and abrogates tumor initiating cell survival. Endocr-Relat Cancer. 2011;18(4):491–503. doi:10.1530/ERC-11-0102.

    PubMed  CAS  Google Scholar 

  51. Zheng Q, Hursting SD, Reizes O. Leptin regulates cyclin D1 in luminal epithelial cells of mouse MMTV-Wnt-1 mammary tumors. J Cancer Res Clin Oncol. 2012. doi:10.1007/s00432-012-1252-9.

    Google Scholar 

  52. Rene Gonzalez R, Watters A, Xu Y, Singh UP, Mann DR, Rueda BR, et al. Leptin-signaling inhibition results in efficient anti-tumor activity in estrogen receptor positive or negative breast cancer. Breast Cancer Res. 2009;11(3):R36.

    PubMed  Google Scholar 

  53. Otvos L, Surmacz E. Targeting the leptin receptor: a potential new mode of treatment for breast cancer. Expert Rev Anticanc. 2011;11(8):1147–50. doi:10.1586/Era.11.109.

    CAS  Google Scholar 

  54. Vona-Davis L, Rose DP. Type 2 diabetes and obesity metabolic interactions: common factors for breast cancer risk and novel approaches to prevention and therapy. Curr Diabetes Rev. 2012;8(2):116–30.

    PubMed  CAS  Google Scholar 

  55. Saxena NK, Taliaferro-Smith L, Knight BB, Merlin D, Anania FA, O’Regan RM, et al. 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. 2008;68(23):9712–22.

    PubMed  CAS  Google Scholar 

  56. Giordano C, Vizza D, Panza S, Barone I, Bonofiglio D, Lanzino M, et al. Leptin increases HER2 protein levels through a STAT3-mediated up-regulation of Hsp90 in breast cancer cells. Mol Oncol. 2013;7(3):379–91. doi:10.1016/j.molonc.2012.11.002.

    PubMed  CAS  Google Scholar 

  57. Barone I, Catalano S, Gelsomino L, Marsico S, Giordano C, Panza S, et al. Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells. Cancer Res. 2012;72(6):1416–27. doi:10.1158/0008-5472.CAN-11-2558.

    PubMed  CAS  Google Scholar 

  58. Ando S, Catalano S. The multifactorial role of leptin in driving the breast cancer microenvironment. Nat Rev Endocrinol. 2012;8(5):263–75. doi:10.1038/nrendo.2011.184.

    CAS  Google Scholar 

  59. Bartella V, Cascio S, Fiorio E, Auriemma A, Russo A, Surmacz E. Insulin-dependent leptin expression in breast cancer cells. Cancer Res. 2008;68(12):4919–27.

    PubMed  CAS  Google Scholar 

  60. Cascio S, Bartella V, Auriemma A, Johannes GJ, Russo A, Giordano A, et al. Mechanism of leptin expression in breast cancer cells: role of hypoxia-inducible factor-1alpha. Oncogene. 2008;27:540–7.

    PubMed  CAS  Google Scholar 

  61. Chen X, Wang Y. Adiponectin and breast cancer. Med Oncol. 2011;28(4):1288–95.

    Google Scholar 

  62. Shibata R, Ouchi N, Murohara T. Adiponectin and cardiovascular disease. Circ J. 2009;73(4):608–14.

    PubMed  CAS  Google Scholar 

  63. Barb D, Williams CJ, Neuwirth AK, Mantzoros CS. Adiponectin in relation to malignancies: a review of existing basic research and clinical evidence. Am J Clin Nutr. 2007;86(3):s858–66.

    PubMed  Google Scholar 

  64. Thundyil J, Pavlovski D, Sobey CG, Arumugam TV. Adiponectin receptor signalling in the brain. Br J Pharmacol. 2012;165(2):313–27. doi:10.1111/j.1476-5381.2011.01560.x.

    PubMed  CAS  Google Scholar 

  65. Wu X, Motoshima H, Mahadev K, Stalker TJ, Scalia R, Goldstein BJ. Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. Diabetes. 2003;52(6):1355–63.

    PubMed  CAS  Google Scholar 

  66. Tsao TS, Tomas E, Murrey HE, Hug C, Lee DH, Ruderman NB, et al. Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity. Different oligomers activate different signal transduction pathways. J Biol Chem. 2003;278(50):50810–7.

    PubMed  CAS  Google Scholar 

  67. Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang Cc C, Itani SI, et al. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci U S A. 2002;99(25):16309–13.

    PubMed  CAS  Google Scholar 

  68. Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol. 2010;316(2):129–39.

    PubMed  CAS  Google Scholar 

  69. Brochu-Gaudreau K, Rehfeldt C, Blouin R, Bordignon V, Murphy BD, Palin MF. Adiponectin action from head to toe. Endocrine. 2010;37(1):11–32.

    PubMed  CAS  Google Scholar 

  70. Hu PF, Bao JP, Wu LD. The emerging role of adipokines in osteoarthritis: a narrative review. Mol Biol Rep. 2010;38(2):873–8.

    PubMed  CAS  Google Scholar 

  71. Ziemke F, Mantzoros CS. Adiponectin in insulin resistance: lessons from translational research. Am J Clin Nutr. 2010;91(1):258S–61S.

    PubMed  CAS  Google Scholar 

  72. Schaffler A, Scholmerich J, Buechler C. Mechanisms of disease: adipokines and breast cancer - endocrine and paracrine mechanisms that connect adiposity and breast cancer. Nat Clin Pract Endocrinol Metab. 2007;3(4):345–54.

    PubMed  Google Scholar 

  73. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003;423(6941):762–9. doi:10.1038/nature01705.

    PubMed  CAS  Google Scholar 

  74. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev. 2005;26(3):439–51.

    PubMed  CAS  Google Scholar 

  75. Wang H, Zhang H, Jia Y, Zhang Z, Craig R, Wang X, et al. Adiponectin receptor 1 gene (ADIPOR1) as a candidate for type 2 diabetes and insulin resistance. Diabetes. 2004;53(8):2132–6.

    PubMed  CAS  Google Scholar 

  76. Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med. 2007;13(3):332–9.

    PubMed  CAS  Google Scholar 

  77. Kadowaki T, Yamauchi T. Adiponectin receptor signaling: a new layer to the current model. Cell Metab. 2011;13(2):123–4.

    PubMed  CAS  Google Scholar 

  78. Wijesekara N, Krishnamurthy M, Bhattacharjee A, Suhail A, Sweeney G, Wheeler MB. Adiponectin-induced ERK and Akt phosphorylation protects against pancreatic beta cell apoptosis and increases insulin gene expression and secretion. J Biol Chem. 2010;285(44):33623–31.

    PubMed  CAS  Google Scholar 

  79. Handy JA, Saxena NK, Fu P, Lin S, Mells JE, Gupta NA, et al. Adiponectin activation of AMPK disrupts leptin-mediated hepatic fibrosis via suppressors of cytokine signaling (SOCS-3). J Cell Biochem. 2010;110(5):1195–207. doi:10.1002/jcb.22634.

    PubMed  CAS  Google Scholar 

  80. Akifusa S, Kamio N, Shimazaki Y, Yamaguchi N, Nonaka K, Yamashita Y. Involvement of the JAK-STAT pathway and SOCS3 in the regulation of adiponectin-generated reactive oxygen species in murine macrophage RAW 264 cells. J Cell Biochem. 2010;111(3):597–606.

    PubMed  CAS  Google Scholar 

  81. Liu J, Lam JB, Chow KH, Xu A, Lam KS, Moon RT, et al. Adiponectin stimulates Wnt inhibitory factor-1 expression through epigenetic regulations involving the transcription factor specificity protein 1. Carcinogenesis. 2008;29(11):2195–202.

    PubMed  CAS  Google Scholar 

  82. Miyazaki T, Bub JD, Uzuki M, Iwamoto Y. Adiponectin activates c-Jun NH2-terminal kinase and inhibits signal transducer and activator of transcription 3. Biochem Biophys Res Commun. 2005;333(1):79–87. doi:10.1016/j.bbrc.2005.05.076.

    PubMed  CAS  Google Scholar 

  83. Korner A, Pazaitou-Panayiotou K, Kelesidis T, Kelesidis I, Williams CJ, Kaprara A, et al. Total and high-molecular-weight adiponectin in breast cancer: in vitro and in vivo studies. J Clin Endocrinol Metab. 2007;92(3):1041–8. doi:10.1210/jc.2006-1858.

    PubMed  Google Scholar 

  84. Hattori Y, Hattori S, Kasai K. Globular adiponectin activates nuclear factor-kappaB in vascular endothelial cells, which in turn induces expression of proinflammatory and adhesion molecule genes. Diabetes Care. 2006;29(1):139–41.

    PubMed  CAS  Google Scholar 

  85. Haugen F, Drevon CA. Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin. Endocrinology. 2007;148(11):5478–86.

    PubMed  CAS  Google Scholar 

  86. Plant S, Shand B, Elder P, Scott R. Adiponectin attenuates endothelial dysfunction induced by oxidised low-density lipoproteins. Diab Vasc Dis Res. 2008;5(2):102–8.

    PubMed  Google Scholar 

  87. Jarde T, Caldefie-Chezet F, Goncalves-Mendes N, Mishellany F, Buechler C, Penault-Llorca F, et al. Involvement of adiponectin and leptin in breast cancer: clinical and in vitro studies. Endocr-Relat Cancer. 2009;16(4):1197–210. doi:10.1677/ERC-09-0043.

    PubMed  CAS  Google Scholar 

  88. Hou WK, Xu YX, Yu T, Zhang L, Zhang WW, Fu CL, et al. Adipocytokines and breast cancer risk. Chin Med J (Engl). 2007;120(18):1592–6.

    CAS  Google Scholar 

  89. Mantzoros C, Petridou E, Dessypris N, Chavelas C, Dalamaga M, Alexe DM, et al. Adiponectin and breast cancer risk. J Clin Endocrinol Metab. 2004;89(3):1102–7.

    PubMed  CAS  Google Scholar 

  90. Macis D, Gandini S, Guerrieri-Gonzaga A, Johansson H, Magni P, Ruscica M, et al. Prognostic effect of circulating adiponectin in a randomized 2 × 2 trial of low-dose tamoxifen and fenretinide in premenopausal women at risk for breast cancer. J Clin Oncol. 2012;30(2):151–7. doi:10.1200/JCO.2011.35.2237.

    PubMed  CAS  Google Scholar 

  91. Saxena NK, Sharma D. Metastasis suppression by adiponectin: LKB1 rises up to the challenge. Cell Adhes Migr. 2010;4(3):358–62.

    Google Scholar 

  92. Arditi JD, Venihaki M, Karalis KP, Chrousos GP. Antiproliferative effect of adiponectin on MCF7 breast cancer cells: a potential hormonal link between obesity and cancer. Horm Metab Res. 2007;39(1):9–13.

    PubMed  CAS  Google Scholar 

  93. Dieudonne MN, Bussiere M, Dos Santos E, Leneveu MC, Giudicelli Y, Pecquery R. Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells. Biochem Biophys Res Commun. 2006;345(1):271–9.

    PubMed  CAS  Google Scholar 

  94. Fujisawa T, Endo H, Tomimoto A, Sugiyama M, Takahashi H, Saito S, et al. Adiponectin suppresses colorectal carcinogenesis under the high-fat diet condition. Gut. 2008;57(11):1531–8.

    PubMed  CAS  Google Scholar 

  95. Grossmann ME, Nkhata KJ, Mizuno NK, Ray A, Cleary MP. Effects of adiponectin on breast cancer cell growth and signaling. Br J Cancer. 2008;98(2):370–9.

    PubMed  CAS  Google Scholar 

  96. Kang JH, Lee YY, Yu BY, Yang BS, Cho KH, Yoon DK, et al. Adiponectin induces growth arrest and apoptosis of MDA-MB-231 breast cancer cell. Arch Pharm Res. 2005;28(11):1263–9.

    PubMed  CAS  Google Scholar 

  97. Dos Santos E, Benaitreau D, Dieudonne MN, Leneveu MC, Serazin V, Giudicelli Y, et al. Adiponectin mediates an antiproliferative response in human MDA-MB 231 breast cancer cells. Oncol Rep. 2008;20(4):971–7.

    PubMed  Google Scholar 

  98. Delort L, Jarde T, Dubois V, Vasson MP, Caldefie-Chezet F. New insights into anticarcinogenic properties of adiponectin: a potential therapeutic approach in breast cancer? Vitam Horm. 2012;90:397–417. doi:10.1016/B978-0-12-398313-8.00015-4.

    PubMed  CAS  Google Scholar 

  99. Otvos Jr L, Haspinger E, La Russa F, Maspero F, Graziano P, Kovalszky I, et al. Design and development of a peptide-based adiponectin receptor agonist for cancer treatment. BMC Biotechnol. 2011;11:90. doi:10.1186/1472-6750-11-90.

    PubMed  CAS  Google Scholar 

  100. Wang Y, Lam JB, Lam KS, Liu J, Lam MC, Hoo RL, et al. Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Res. 2006;66(23):11462–70. doi:10.1158/0008-5472.CAN-06-1969.

    PubMed  CAS  Google Scholar 

  101. Taliaferro-Smith L, Nagalingam A, Zhong D, Zhou W, Saxena NK, Sharma D. LKB1 is required for adiponectin-mediated modulation of AMPK-S6K axis and inhibition of migration and invasion of breast cancer cells. Oncogene. 2009;28(29):2621–33.

    PubMed  CAS  Google Scholar 

  102. Saxena NK, Sharma D. Metastasis suppression by adiponectin: LKB1 rises up to the challenge. Cell Adh Migr. 2010;4(3):358–62.

    Google Scholar 

  103. Ouchi N, Kobayashi H, Kihara S, Kumada M, Sato K, Inoue T, et al. Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J Biol Chem. 2004;279(2):1304–9. doi:10.1074/jbc.M310389200.

    PubMed  CAS  Google Scholar 

  104. Zhao HY, Zhao M, Yi TN, Zhang J. Globular adiponectin protects human umbilical vein endothelial cells against apoptosis through adiponectin receptor 1/adenosine monophosphate-activated protein kinase pathway. Chin Med J (Engl). 2011;124(16):2540–7.

    CAS  Google Scholar 

  105. Lam JB, Chow KH, Xu A, Lam KS, Liu J, Wong NS, et al. Adiponectin haploinsufficiency promotes mammary tumor development in MMTV-PyVT mice by modulation of phosphatase and tensin homolog activities. PloS One. 2009;4(3):e4968. doi:10.1371/journal.pone.0004968.

    PubMed  Google Scholar 

  106. Dubois V, Delort L, Billard H, Vasson MP, Caldefie-Chezet F. Breast cancer and obesity: in vitro interferences between adipokines and proangiogenic features and/or antitumor therapies? PloS One. 2013;8(3):e58541. doi:10.1371/journal.pone.0058541.

    PubMed  CAS  Google Scholar 

  107. Pfeiler G, Hudelist G, Wulfing P, Mattsson B, Konigsberg R, Kubista E, et al. Impact of AdipoR1 expression on breast cancer development. Gynecol Oncol. 2010;117(1):134–8.

    PubMed  CAS  Google Scholar 

  108. Pfeiler G, Treeck O, Wenzel G, Goerse R, Hartmann A, Schmitz G, et al. Influence of insulin resistance on adiponectin receptor expression in breast cancer. Maturitas. 2009;63(3):253–6. doi:10.1016/j.maturitas.2009.04.006.

    PubMed  CAS  Google Scholar 

  109. Takahata C, Miyoshi Y, Irahara N, Taguchi T, Tamaki Y, Noguchi S. Demonstration of adiponectin receptors 1 and 2 mRNA expression in human breast cancer cells. Cancer Lett. 2007;250(2):229–36.

    PubMed  CAS  Google Scholar 

  110. Nakayama S, Miyoshi Y, Ishihara H, Noguchi S. Growth-inhibitory effect of adiponectin via adiponectin receptor 1 on human breast cancer cells through inhibition of S-phase entry without inducing apoptosis. Breast Cancer Res Treat. 2008;112(3):405–10.

    PubMed  CAS  Google Scholar 

  111. Ollberding NJ, Kim Y, Shvetsov YB, Wilkens LR, Franke AA, Cooney RV, et al. Prediagnostic leptin, adiponectin, C-reactive protein, and the risk of postmenopausal breast cancer. Cancer Prev Res (Phila). 2013;6(3):188–95. doi:10.1158/1940-6207.CAPR-12-0374.

    CAS  Google Scholar 

  112. Taliaferro-Smith L, Nagalingam A, Knight BB, Oberlick E, Saxena NK, Sharma D. Integral role of PTP1B in adiponectin-mediated inhibition of oncogenic actions of leptin in breast carcinogenesis. Neoplasia. 2013;15(1):23–38.

    PubMed  CAS  Google Scholar 

  113. Fabian CJ. Adiponectin: a risk biomarker and attractive target for chemoprevention. J Clin Oncol. 2012;30(2):124–6. doi:10.1200/JCO.2011.38.5500.

    PubMed  CAS  Google Scholar 

  114. Perrier S, Jarde T. Adiponectin, an anti-carcinogenic hormone? A systematic review on breast, colorectal, liver and prostate cancer. Curr Med Chem. 2012;19(32):5501–12.

    PubMed  CAS  Google Scholar 

  115. Jalving M, Gietema JA, Lefrandt JD, de Jong S, Reyners AK, Gans RO, et al. Metformin: taking away the candy for cancer? Eur J Cancer. 2010;46(13):2369–80. doi:10.1016/j.ejca.2010.06.012.

    PubMed  CAS  Google Scholar 

  116. Gonzalez RR, Cherfils S, Escobar M, Yoo JH, Carino C, Styer AK, et al. 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. 2006;281(36):26320–8.

    PubMed  CAS  Google Scholar 

  117. Gonzalez RR, Leavis PC. A peptide derived from the human leptin molecule is a potent inhibitor of the leptin receptor function in rabbit endometrial cells. Endocrine. 2003;21(2):185–95.

    PubMed  CAS  Google Scholar 

  118. Ramos MP, Rueda BR, Leavis PC, Gonzalez RR. Leptin serves as an upstream activator of an obligatory signaling cascade in the embryo-implantation process. Endocrinology. 2005;146(2):694–701. doi:10.1210/en.2004-1186.

    PubMed  CAS  Google Scholar 

  119. Garonna E, Botham KM, Birdsey GM, Randi AM, Gonzalez-Perez RR, Wheeler-Jones CP. Vascular endothelial growth factor receptor-2 couples cyclo-oxygenase-2 with pro-angiogenic actions of leptin on human endothelial cells. PloS One. 2011;6(4):e18823. doi:10.1371/journal.pone.0018823.

    PubMed  CAS  Google Scholar 

  120. Otvos Jr L, Terrasi M, Cascio S, Cassone M, Abbadessa G, De Pascali F, et al. Development of a pharmacologically improved peptide agonist of the leptin receptor. Biochim Biophys Acta. 2008;1783(10):1745–54. doi:10.1016/j.bbamcr.2008.05.007.

    PubMed  CAS  Google Scholar 

  121. Otvos Jr L, Kovalszky I, Scolaro L, Sztodola A, Olah J, Cassone M, et al. Peptide-based leptin receptor antagonists for cancer treatment and appetite regulation. Biopolymers. 2011;96(2):117–25. doi:10.1002/bip.21377.

    PubMed  CAS  Google Scholar 

  122. Napoleone E, Cutrone A, Cugino D, Latella MC, Zurlo F, Iacoviello L, et al. Leptin upregulates tissue factor expression in human breast cancer MCF-7 cells. Thromb Res. 2012;129(5):641–7. doi:10.1016/j.thromres.2011.07.037.

    PubMed  CAS  Google Scholar 

  123. Fusco R, Galgani M, Procaccini C, Franco R, Pirozzi G, Fucci L, et al. Cellular and molecular crosstalk between leptin receptor and estrogen receptor-{alpha} in breast cancer: molecular basis for a novel therapeutic setting. Endocr-Relat Cancer. 2010;17(2):373–82. doi:10.1677/ERC-09-0340.

    PubMed  CAS  Google Scholar 

  124. Fazeli M, Zarkesh-Esfahani H, Wu Z, Maamra M, Bidlingmaier M, Pockley AG, et al. Identification of a monoclonal antibody against the leptin receptor that acts as an antagonist and blocks human monocyte and T cell activation. J Immunol Methods. 2006;312(1–2):190–200. doi:10.1016/j.jim.2006.03.011.

    PubMed  CAS  Google Scholar 

  125. Zeidan A, Purdham DM, Rajapurohitam V, Javadov S, Chakrabarti S, Karmazyn M. Leptin induces vascular smooth muscle cell hypertrophy through angiotensin II- and endothelin-1-dependent mechanisms and mediates stretch-induced hypertrophy. J Pharmacol Exp Ther. 2005;315(3):1075–84.

    PubMed  CAS  Google Scholar 

  126. Zeidan A, Javadov S, Chakrabarti S, Karmazyn M. Leptin-induced cardiomyocyte hypertrophy involves selective caveolae and RhoA/ROCK-dependent p38 MAPK translocation to nuclei. Cardiovasc Res. 2008;77(1):64–72.

    PubMed  CAS  Google Scholar 

  127. Saxena NK, Vertino PM, Anania FA, Sharma D. leptin-induced growth stimulation of breast cancer cells involves recruitment of histone acetyltransferases and mediator complex to CYCLIN D1 promoter via activation of Stat3. J Biol Chem. 2007;282(18):13316–25. doi:10.1074/jbc.M609798200.

    PubMed  CAS  Google Scholar 

  128. Yin N, Wang D, Zhang H, Yi X, Sun X, Shi B, et al. Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin. Cancer Res. 2004;64(16):5870–5. doi:10.1158/0008-5472.CAN-04-0655.

    PubMed  CAS  Google Scholar 

  129. Soma D, Kitayama J, Yamashita H, Miyato H, Ishikawa M, Nagawa H. Leptin augments proliferation of breast cancer cells via transactivation of HER2. J Surg Res. 2008;149(1):9–14. doi:10.1016/j.jss.2007.10.012.

    PubMed  CAS  Google Scholar 

  130. Jiang H, Yu J, Guo H, Song H, Chen S. Upregulation of survivin by leptin/STAT3 signaling in MCF-7 cells. Biochem Biophys Res Commun. 2008;368(1):1–5.

    PubMed  CAS  Google Scholar 

  131. Catalano S, Marsico S, Giordano C, Mauro L, Rizza P, Panno ML, et al. Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line. J Biol Chem. 2003;278(31):28668–76.

    PubMed  CAS  Google Scholar 

  132. El-Masry OS, Brown BL, Dobson PR. Effects of activation of AMPK on human breast cancer cell lines with different genetic backgrounds. Oncol Lett. 2012;3(1):224–8. doi:10.3892/ol.2011.458.

    PubMed  CAS  Google Scholar 

  133. Swinnen JV, Beckers A, Brusselmans K, Organe S, Segers J, Timmermans L, et al. Mimicry of a cellular low energy status blocks tumor cell anabolism and suppresses the malignant phenotype. Cancer Res. 2005;65(6):2441–8. doi:10.1158/0008-5472.CAN-04-3025.

    PubMed  CAS  Google Scholar 

  134. Youn SH, Lee JS, Lee MS, Cha EY, Thuong PT, Kim JR, et al. Anticancer properties of pomolic acid-induced AMP-activated protein kinase activation in MCF7 human breast cancer cells. Biol Pharm Bull. 2012;35(1):105–10.

    PubMed  CAS  Google Scholar 

  135. Bosi E. Metformin–the gold standard in type 2 diabetes: what does the evidence tell us? Diabetes Obes Metab. 2009;11 Suppl 2:3–8.

    PubMed  CAS  Google Scholar 

  136. Boyle JG, Salt IP, McKay GA. Metformin action on AMP-activated protein kinase: a translational research approach to understanding a potential new therapeutic target. Diabet Med. 2010;27(10):1097–106.

    PubMed  CAS  Google Scholar 

  137. Janjetovic K, Vucicevic L, Misirkic M, Vilimanovich U, Tovilovic G, Zogovic N, et al. Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt. Eur J Pharmacol. 2011;651(1–3):41–50.

    PubMed  CAS  Google Scholar 

  138. Miller RA, Birnbaum MJ. An energetic tale of AMPK-independent effects of metformin. J Clin Invest. 2010;120(7):2267–70.

    Google Scholar 

  139. Hardie DG. The AMP-activated protein kinase pathway–new players upstream and downstream. J Cell Sci. 2004;117(Pt 23):5479–87.

    PubMed  CAS  Google Scholar 

  140. Deng XS, Wang S, Deng A, Liu B, Edgerton SM, Lind SE, et al. Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle. 2012;11(2):367–76. doi:10.4161/cc.11.2.18813.

    PubMed  CAS  Google Scholar 

  141. Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del Barco S, Martin-Castillo B, Lopez-Bonet E, et al. The anti-diabetic drug metformin suppresses the metastasis-associated protein CD24 in MDA-MB-468 triple-negative breast cancer cells. Oncol Rep. 2011;25(1):135–40.

    PubMed  CAS  Google Scholar 

  142. Koh M, Lee JC, Min C, Moon A. A novel metformin derivative, HL010183, inhibits proliferation and invasion of triple-negative breast cancer cells. Bioorg Med Chem. 2013;21(8):2305–13. doi:10.1016/j.bmc.2013.02.015.

    PubMed  CAS  Google Scholar 

  143. Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. Cell Cycle. 2009;8(1):88–96.

    PubMed  CAS  Google Scholar 

  144. Anisimov VN. Metformin for aging and cancer prevention. Aging (Albany NY). 2010;2(11):760–74.

    CAS  Google Scholar 

  145. Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, Bost F. Metformin in cancer therapy: a new perspective for an old antidiabetic drug? Mol Cancer Ther. 2010;9(5):1092–9. doi:10.1158/1535-7163.MCT-09-1186.

    PubMed  CAS  Google Scholar 

  146. Gonzalez-Angulo AM, Meric-Bernstam F. Metformin: a therapeutic opportunity in breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2010;16(6):1695–700.

    CAS  Google Scholar 

  147. Kourelis TV, Siegel RD. Metformin and cancer: new applications for an old drug. Med Oncol. 2012;29(2):1314–27.

    Google Scholar 

  148. Pollak M. Metformin and other biguanides in oncology: advancing the research agenda. Cancer Prev Res (Phila). 2010;3(9):1060–5.

    CAS  Google Scholar 

  149. Hadad SM, Fleming S, Thompson AM. Targeting AMPK: a new therapeutic opportunity in breast cancer. Crit Rev Oncol Hematol. 2008;67(1):1–7.

    PubMed  Google Scholar 

  150. Aksoy S, Sendur MA, Altundag K. Demographic and clinico-pathological characteristics in patients with invasive breast cancer receiving metformin. Med Oncol. 2013;30(2):590. doi:10.1007/s12032-013-0590-z.

    PubMed  Google Scholar 

  151. Zhu Z, Jiang W, Thompson MD, McGinley JN, Thompson HJ. Metformin as an energy restriction mimetic agent for breast cancer prevention. J Carcinog. 2011;10:17.

    PubMed  CAS  Google Scholar 

  152. Bayraktar S, Hernadez-Aya LF, Lei X, Meric-Bernstam F, Litton JK, Hsu L, et al. Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer. Cancer. 2012;118(5):1202–11. doi:10.1002/cncr.26439.

    PubMed  CAS  Google Scholar 

  153. Jonas D, Van Scoyoc E, Gerrald K, Wines R, Amick H, Triplette M, et al. Drug Class Review: Newer Diabetes Medications, TZDs, and Combinations: Final Original Report. Drug Class Reviews. Portland (OR)2011.

  154. Kahn CR, Chen L, Cohen SE. Unraveling the mechanism of action of thiazolidinediones. J Clin Investig. 2000;106(11):1305–7. doi:10.1172/JCI11705.

    PubMed  CAS  Google Scholar 

  155. Catalano S, Mauro L, Bonofiglio D, Pellegrino M, Qi H, Rizza P, et al. In vivo and in vitro evidence that PPARgamma ligands are antagonists of leptin signaling in breast cancer. Am J Pathol. 2011;179(2):1030–40. doi:10.1016/j.ajpath.2011.04.026.

    PubMed  CAS  Google Scholar 

  156. Terrasi M, Bazan V, Caruso S, Insalaco L, Amodeo V, Fanale D, et al. Effects of PPARgamma agonists on the expression of leptin and vascular endothelial growth factor in breast cancer cells. J Cell Physiol. 2013;228(6):1368–74. doi:10.1002/jcp.24295.

    PubMed  CAS  Google Scholar 

  157. Koda M, Kanczuga-Koda L, Sulkowska M, Surmacz E, Sulkowski S. Relationships between hypoxia markers and the leptin system, estrogen receptors in human primary and metastatic breast cancer: effects of preoperative chemotherapy. BMC Cancer. 2010;10:320. doi:10.1186/1471-2407-10-320.

    PubMed  Google Scholar 

  158. Otvos Jr L, Cassone M, Terrasi M, Cascio S, Mateo GD, Knappe D, et al. Agonists and partial antagonists acting on the leptin–leptin receptor interface. Adv Exp Med Biol. 2009;611:497–8.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, 1900 N12th Street, BioLife Bldg. Rm 425, Philadelphia, PA, 19122, USA

    Eva Surmacz

Authors
  1. Eva Surmacz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eva Surmacz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Surmacz, E. Leptin and Adiponectin: Emerging Therapeutic Targets in Breast Cancer. J Mammary Gland Biol Neoplasia 18, 321–332 (2013). https://doi.org/10.1007/s10911-013-9302-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-013-9302-8

Keywords

Search

Navigation