Clinical & Experimental Metastasis

, Volume 26, Issue 3, pp 197–204 | Cite as

Leptin utilizes Jun N-terminal kinases to stimulate the invasion of MCF-7 breast cancer cells

  • Vanity McMurtry
  • Ann-Marie Simeone
  • René Nieves-Alicea
  • Ana M. Tari
Research Paper

Abstract

In breast tumors, high levels of leptin have been associated with increased incidence of breast cancer metastasis. Breast cancer metastasis is directly associated with breast cancer cell invasion. However, whether leptin could augment breast cancer cell invasion is not known. Here we showed that leptin increased the invasiveness and the matrix metallo-proteinase-2 (MMP-2) activity of the MCF-7 breast cancer cell line. Leptin stimulated the phosphorylation of extracellular signals regulated kinases, signal transducers and activators of transcription 3 and Jun N-terminal kinases (JNK); however, only inhibition of JNK decreased leptin-mediated activation of MMP-2. Furthermore, inhibition of JNK suppressed leptin-mediated breast cancer cell invasion. Here we report the novel findings that leptin increased invasion of breast cancer cells by activating JNK, resulting in increased MMP-2 activity.

Keywords

Breast cancer invasion Extracellular signals regulated kinases Jun N-terminal kinases Leptin Matrix metallo-proteinase-2 Signal transducers and activators of transcription 3 

Abbreviations

DMEM/F-12

Dulbecco’s Modified Eagle’s Medium/Nutrient Mixture F-12

ERK

Extracellular signals regulated kinases

JAK2

Janus-activated kinase 2

JNK

Jun N-terminal kinases

MMPs

Metalloproteinases

SRC

Sarcoma oncogene

STAT3

Signal transducers and activators of transcription 3

Notes

Acknowledgments

This research was supported in part by the Cancer Research and Prevention Foundation (to A.-M. Simeone) and by the Susan G. Komen Breast Cancer Foundation (to A. M. Tari).

References

  1. 1.
    McTiernan A (2000) Associations between energy balance and body mass index and risk of breast carcinoma in women from diverse racial and ethnic backgrounds in the U.S. Cancer 88:1248–1255. doi:10.1002/(SICI)1097-0142(20000301)88:5+<1248::AID-CNCR12>3.0.CO;2-1PubMedCrossRefGoogle Scholar
  2. 2.
    Trentham-Dietz A, Newcomb PA, Egan KM et al (2000) Weight change and risk of postmenopausal breast cancer (United States). Cancer Causes Control 11:533–542. doi:10.1023/A:1008961931534 PubMedCrossRefGoogle Scholar
  3. 3.
    Petrelli JM, Calle EE, Rodriguez C et al (2002) Body mass index, height, and postmenopausal breast cancer mortality in a prospective cohort of US women. Cancer Causes Control 13:325–332. doi:10.1023/A:1015288615472 PubMedCrossRefGoogle Scholar
  4. 4.
    Morimoto LM, White E, Chen Z et al (2002) Obesity, body size, and risk of postmenopausal breast cancer: the women’s health initiative (United States). Cancer Causes Control 13:741–751. doi:10.1023/A:1020239211145 PubMedCrossRefGoogle Scholar
  5. 5.
    Calle EE, Rodriguez C, Walker-Thurmond K et al (2003) Overweight, obesity and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625–1638. doi:10.1056/NEJMoa021423 PubMedCrossRefGoogle Scholar
  6. 6.
    Porter GA, Inglis KM, Wood LA et al (2006) Effect of obesity on presentation of breast cancer. Ann Surg Oncol 13:327–332. doi:10.1245/ASO.2006.03.049 PubMedCrossRefGoogle Scholar
  7. 7.
    Verreault R, Brisson J, Deschenes L et al (1989) Body weight and prognostic indicators in breast cancer modifying effect of estrogen receptors. Am J Epidemiol 129:260–268PubMedGoogle Scholar
  8. 8.
    Giuffrida D, Lupo L, La Porta GA et al (1992) Relation between steroid receptor status and body weight in breast cancer patients. Eur J Cancer 28:112–115. doi:10.1016/0959-8049(92)90397-K PubMedCrossRefGoogle Scholar
  9. 9.
    Huang WY, Newman B, Millikan RC (2000) Hormone-related factors and risk of breast cancer in relation to estrogen receptor and progesterone receptor status. Am J Epidemiol 151:703–714PubMedGoogle Scholar
  10. 10.
    Zhang Y, Proenca R, Maffei M et al (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432. doi:10.1038/372425a0 PubMedCrossRefGoogle Scholar
  11. 11.
    Sinha MK, Opentanova I, Ohannesian JP et al (1996) Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. J Clin Invest 98:1277–1282. doi:10.1172/JCI118913 PubMedCrossRefGoogle Scholar
  12. 12.
    McGregor GP, Desaga JF, Ehlenz K et al (1996) Radiommunological measurement of leptin in plasma of obese and diabetic human subjects. Endocrinology 137:1501–1504. doi:10.1210/en.137.4.1501 PubMedCrossRefGoogle Scholar
  13. 13.
    Ishikawa M, Kitayama J, Nagawa H (2004) Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res 10:4325–4331. doi:10.1158/1078-0432.CCR-03-0749 PubMedCrossRefGoogle Scholar
  14. 14.
    Miyoshi Y, Funahashi T, Tanaka S et al (2006) 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 118:1414–1419. doi:10.1002/ijc.21543 PubMedCrossRefGoogle Scholar
  15. 15.
    Caldefie-Chezet F, Damez M, de Latour M et al (2005) Leptin: a proliferative factor for breast cancer? Study on human ductal carcinoma. Biochem Biophys Res Commun 334:737–741. doi:10.1016/j.bbrc.2005.06.077 PubMedCrossRefGoogle Scholar
  16. 16.
    Garofalo C, Koda M, Cascio S et al (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. doi:10.1158/1078-0432.CCR-05-1913 PubMedCrossRefGoogle Scholar
  17. 17.
    Revillion F, Charlier M, Lhotellier V et al (2006) Messenger RNA expression of leptin and leptin receptors and their prognostic value in 322 human primary breast cancers. Clin Cancer Res 12:2088–2094. doi:10.1158/1078-0432.CCR-05-1904 PubMedCrossRefGoogle Scholar
  18. 18.
    Hu X, Juneja SC, Maihle NJ et al (2002) Leptin–a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 94:1704–1711PubMedGoogle Scholar
  19. 19.
    Yin N, Wang D, Zhang H et al (2004) Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin. Cancer Res 64:5870–5875. doi:10.1158/0008-5472.CAN-04-0655 PubMedCrossRefGoogle Scholar
  20. 20.
    Chen C, Chang YC, Liu CL et al (2006) Leptin-induced growth of human ZR-75-1 breast cancer cells is associated with up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21WAF1/CIP1. Breast Cancer Res Treat 98:121–132. doi:10.1007/s10549-005-9139-y PubMedCrossRefGoogle Scholar
  21. 21.
    Saxena NK, Vertino PM, Anania FA et al (2007) 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 282:13316–13325. doi:10.1074/jbc.M609798200 PubMedCrossRefGoogle Scholar
  22. 22.
    Mauro L, Catalano S, Bossi G et al (2007) Evidences that leptin up-regulates E-cadherin expression in breast cancer: effects on tumor growth and progression. Cancer Res 67:3412–3421. doi:10.1158/0008-5472.CAN-06-2890 PubMedCrossRefGoogle Scholar
  23. 23.
    Ray A, Nkhata KJ, Cleary MP (2007) Effects of leptin on human breast cancer cell lines in relationship to estrogen receptor and HER2 status. Int J Oncol 30:1499–1509PubMedGoogle Scholar
  24. 24.
    Jiang H, Yu J, Guo H et al (2008) Upregulation of survivin by leptin/STAT3 signaling in MCF-7 cells. Biochem Biophys Res Commun 368:1–5. doi:10.1016/j.bbrc.2007.04.004 PubMedCrossRefGoogle Scholar
  25. 25.
    Cleary MP, Juneja SC, Phillips FC et al (2004) Leptin receptor-deficient MMTV-TGF-alpha/Lepr(db)Lepr(db) female mice do not develop oncogene-induced mammary tumors. Exp Biol Med (Maywood) 229:182–193Google Scholar
  26. 26.
    Gonzalez RR, Cherfils S, Escobar M et al (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. doi:10.1074/jbc.M601991200 PubMedCrossRefGoogle Scholar
  27. 27.
    Catalano S, Marsico S, Giordano C et al (2003) Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line. J Biol Chem 278:28668–28676. doi:10.1074/jbc.M301695200 PubMedCrossRefGoogle Scholar
  28. 28.
    Catalano S, Mauro L, Marsico S et al (2004) Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor alpha in MCF-7 cells. J Biol Chem 279:19908–19915. doi:10.1074/jbc.M313191200 PubMedCrossRefGoogle Scholar
  29. 29.
    Garofalo C, Sisci D, 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. doi:10.1158/1078-0432.CCR-04-0203 PubMedCrossRefGoogle Scholar
  30. 30.
    Attoub S, Noe V, Pirola L et al (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. doi:10.1096/fj.00-0162 PubMedCrossRefGoogle Scholar
  31. 31.
    Schulz LC, Widmaier EP (2004) The effect of leptin on mouse trophoblast cell invasion. Biol Reprod 71:1963–1967. doi:10.1095/biolreprod.104.032722 PubMedCrossRefGoogle Scholar
  32. 32.
    Horiguchi A, Sumitomo M, Asakuma J et al (2006) Leptin promotes invasiveness of murine renal cancer cells via extracellular signal-regulated kinases and rho dependent pathway. J Urol 176:1636–1641. doi:10.1016/j.juro.2006.06.040 PubMedCrossRefGoogle Scholar
  33. 33.
    Sharma D, Saxena NK, Vertino PM et al (2006) Leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal-transduction pathways. Endocr Relat Cancer 13:629–640. doi:10.1677/erc.1.01169 PubMedCrossRefGoogle Scholar
  34. 34.
    Saxena NK, Sharma D, Ding X et al (2007) Concomitant activation of the JAK/STAT, PI3 K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res 67:2497–2507. doi:10.1158/0008-5472.CAN-06-3075 PubMedCrossRefGoogle Scholar
  35. 35.
    Zhu Y, Wang A, Liu MC et al (2006) Estrogen receptor alpha positive breast tumors and breast cancer cell lines share similarities in their transcriptome data structures. Int J Oncol 29:1581–1589PubMedGoogle Scholar
  36. 36.
    Iwata H, Kobayashi S, Iwase H et al (1996) Production of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human breast carcinomas. Jpn J Cancer Res 87:602–611PubMedGoogle Scholar
  37. 37.
    Lee KS, Rha SY, Kim SJ et al (1996) Sequential activation and production of matrix metalloproteinase-2 during breast cancer progression. Clin Exp Metastasis 14:512–519. doi:10.1007/BF00115111 PubMedCrossRefGoogle Scholar
  38. 38.
    Rha SY, Kim JH, Roh JK et al (1997) Sequential production and activation of matrix-metalloproteinase-9 (MMP-9) with breast cancer progression. Breast Cancer Res Treat 43:175–181. doi:10.1023/A:1005701231871 PubMedCrossRefGoogle Scholar
  39. 39.
    Jones JL, Glynn P, Walker RA (1999) Expression of MMP-2 and MMP-9, their inhibitors, and the activator MT1-MMP in primary breast carcinomas. J Pathol 189:161–168. doi:10.1002/(SICI)1096-9896(199910)189:2<161::AID-PATH406>3.0.CO;2-2PubMedCrossRefGoogle Scholar
  40. 40.
    Castellucci M, De Matteis R, Meisser A et al (2000) Leptin modulates extracellular matrix molecules and metalloproteinases: possible implications for trophoblast invasion. Mol Hum Reprod 6:951–958. doi:10.1093/molehr/6.10.951 PubMedCrossRefGoogle Scholar
  41. 41.
    Desouki MM, Rowan BG (2004) SRC kinase and mitogen-activated protein kinases in the progression from normal to malignant endometrium. Clin Cancer Res 10:546–555. doi:10.1158/1078-0432.CCR-0661-03 PubMedCrossRefGoogle Scholar
  42. 42.
    Le YJ, Corry PM (1999) Hypoxia-induced bFGF gene expression is mediated through the JNK signal transduction pathway. Mol Cell Biochem 202:1–8. doi:10.1023/A:1007059806016 PubMedCrossRefGoogle Scholar
  43. 43.
    Luo J (2006) Role of matrix metalloproteinase-2 in ethanol-induced invasion by breast cancer cells. J Gastroenterol Hepatol 21(Suppl 3):S65–S68. doi:10.1111/j.1440-1746.2006.04578.x PubMedCrossRefGoogle Scholar
  44. 44.
    Serrati S, Margheri F, Fibbi G et al (2007) Endothelial cells and normal breast epithelial cells enhance invasion of breast carcinoma cells by CXCR-4-dependent up-regulation of urokinase-type plasminogen activator receptor (uPAR, CD87) expression. J Pathol 214(5):545–554CrossRefGoogle Scholar
  45. 45.
    Onuma M, Bub JD, Rummel TL et al (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. doi:10.1074/jbc.M304984200 PubMedCrossRefGoogle Scholar
  46. 46.
    Ogunwobi O, Mutungi G, Beales IL (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 147:4505–4516. doi:10.1210/en.2006-0224 PubMedCrossRefGoogle Scholar
  47. 47.
    Ogunwobi OO, Beales IL (2007) The anti-apoptotic and growth stimulatory actions of leptin in human colon cancer cells involves activation of JNK mitogen activated protein kinase, JAK2 and PI3 kinase/Akt. Int J Colorectal Dis 22:401–409. doi:10.1007/s00384-006-0181-y PubMedCrossRefGoogle Scholar
  48. 48.
    Jacobs C, Rubsamen H (1983) Expression of pp60c-src protein kinase in adult and fetal human tissue: high activities in some sarcomas and mammary carcinomas. Cancer Res 43:1696–1702PubMedGoogle Scholar
  49. 49.
    Rosen N, Bolen JB, Schwartz AM et al (1986) Analysis of pp60c-src protein kinase activity in human tumor cell lines and tissues. J Biol Chem 261:13754–13759PubMedGoogle Scholar
  50. 50.
    Ottenhoff-Kalff AE, Rijksen G, van Beurden EA et al (1992) Characterization of protein tyrosine kinases from human breast cancer: involvement of the c-src oncogene product. Cancer Res 52:4773–4778PubMedGoogle Scholar
  51. 51.
    Myoui A, Nishimura R, Williams PJ et al (2003) C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Cancer Res 63:5028–5033PubMedGoogle Scholar
  52. 52.
    Rucci N, Recchia I, Angelucci A et al (2006) Inhibition of protein kinase c-Src reduces the incidence of breast cancer metastases and increases survival in mice: implications for therapy. J Pharmacol Exp Ther 318:161–172. doi:10.1124/jpet.106.102004 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Vanity McMurtry
    • 1
  • Ann-Marie Simeone
    • 1
  • René Nieves-Alicea
    • 1
  • Ana M. Tari
    • 1
  1. 1.Department of Experimental TherapeuticsThe University of Texas M. D. Anderson Cancer CenterHoustonUSA

Personalised recommendations