Skip to main content

Antagonism of the prostaglandin E receptor EP4 inhibits metastasis and enhances NK function

Breast Cancer Research and Treatment volume 117, pages 235–242 (2009)Cite this article

Abstract

Cyclooxygenase-2 (COX-2) is associated with aggressive breast cancers. The COX-2 product prostaglandin E2 (PGE2) acts through four G-protein-coupled receptors designated EP1–4. Malignant and immortalized normal mammary epithelial cell lines express all four EP. The EP4 antagonist AH23848 reduced the ability of tumor cells to colonize the lungs or to spontaneously metastasize from the mammary gland. EP4 gene silencing by shRNA also reduced the ability of mammary tumor cells to metastasize. Metastasis inhibition was lost in mice lacking either functional Natural Killer (NK) cells or interferon-γ. EP4 antagonism inhibited MHC class I expression resulting in enhanced ability of NK cells to lyse mammary tumor target cells. These studies support the hypothesis that EP4 receptor antagonists reduce metastatic potential by facilitating NK-mediated tumor cell killing and that therapeutic targeting of EP4 may be an alternative approach to the use of COX inhibitors to limit metastatic disease.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Bennett A, Charlier EM, McDonald AM, Simpson JS, Stanford IF (1977) Prostaglandin and breast cancer. Lancet 2:624–626. doi:10.1016/S0140-6736(77)92496-5

    PubMed  Article  CAS  Google Scholar 

  2. Ristimaki A, Sivula A, Lundin M et al (2002) Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 62:632–635

    PubMed  CAS  Google Scholar 

  3. Thun MJ, Namboodiri MM, Calle EE, Flanders WD, Heath CW Jr (1993) Aspirin use and risk of fatal cancer. Cancer Res 53:1322–1327

    PubMed  CAS  Google Scholar 

  4. Harris RE, Beebe-Donk J, Alshafie GA (2006) Reduction of the risk of human breast cancer by selective cyclooxygenase-2 [COX-2] inhibitors. BMC Cancer 6:27–31. doi:10.1186/1471-2407-6-27

    PubMed  Article  Google Scholar 

  5. Sheng H, Shao J, Morrow JD, Beauchamp RD, DuBois RN (1998) Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res 58:362–366

    PubMed  CAS  Google Scholar 

  6. Tsujii M, Kawano S, Tsujii S, Sawaoka H, Hori H, DuBois RN (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705–716. doi:10.1016/S0092-8674(00)81433-6

    PubMed  Article  CAS  Google Scholar 

  7. Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner M et al (2000) Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60:1306–1311

    PubMed  CAS  Google Scholar 

  8. Goodwin JS, Ceuppens J (1983) Regulation of the immune response by prostaglandins. J Clin Immunol 3:295–315. doi:10.1007/BF00915791

    PubMed  Article  CAS  Google Scholar 

  9. Fulton AM, Heppner GH (1985) Relationships of prostaglandin E and Natural Killer sensitivity to metastatic potential in murine mammary adenocarcinomas. Cancer Res 45:4779–4784

    PubMed  CAS  Google Scholar 

  10. Lala PK, Parhar RS, Singh P (1986) Indomethacin therapy abrogates the prostaglandin-mediated suppression of Natural Killer activity in tumor-bearing mice and prevents tumor metastasis. Cell Immunol 99:108–118. doi:10.1016/0008-8749(86)90220-0

    PubMed  Article  CAS  Google Scholar 

  11. Stolina M, Sharma S, Lin Y et al (2000) Specific inhibition of cyclooxygenase-2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol 164:361–370

    PubMed  CAS  Google Scholar 

  12. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S (2007) Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 67:4507–4513. doi:10.1158/0008-5472.CAN-06-4174

    PubMed  Article  CAS  Google Scholar 

  13. Wang D, Wang M, Cheng Y, Fitzgerald GA (2005) Cardiovascular hazard and nonsteroidal anti-inflammatory drugs. Curr Opin Pharmacol 2:204–210. doi:10.1016/j.coph.2005.02.001

    Article  Google Scholar 

  14. Narumiya S, Sugimoto Y, Ushikubi F (1999) Prostanoid receptors: structures properties and functions. Physiol Rev 79:1193–1226

    PubMed  CAS  Google Scholar 

  15. Ma X, Kundu N, Rifat S, Walser T, Fulton AM (2006) Prostaglandin E receptor EP4 antagonism inhibits breast cancer metastasis. Cancer Res 66:2923–2927. doi:10.1158/0008-5472.CAN-05-4348

    PubMed  Article  CAS  Google Scholar 

  16. Kundu N, Walser TC, Ma X, Fulton AM (2005) Cyclooxygenase inhibitors modulate NK activities that control metastatic disease. Cancer Immunol Immunother 54:981–987. doi:10.1007/s00262-005-0669-2

    PubMed  Article  CAS  Google Scholar 

  17. Kundu N, Yang Q, Dorsey R, Fulton AM (2001) Increased cyclooxygenase-2 [COX-2] expression and activity in a murine model of metastatic breast cancer. Int J Cancer 93:681–686. doi:10.1002/ijc.1397

    PubMed  Article  CAS  Google Scholar 

  18. Kundu N, Fulton AM (2002) Selective cyclooxygenase [COX]-1 or COX-2 inhibitors control metastatic disease in a murine model of breast cancer. Cancer Res 62:2343–2346

    PubMed  CAS  Google Scholar 

  19. Watanabe T, Satoh H, Togoh M, Taniguchi S, Hashimoto Y, Kurokawa K (1996) Positive and negative regulation of cell proliferation through prostaglandin receptors in NIH-3T3 cells. J Cell Physiol 69:401–409. doi :10.1002/(SICI)1097-4652(199611)169:2<401::AID-JCP20>3.0.CO;2-A

    Article  Google Scholar 

  20. Cherukuri DP, Chen XBO, Goulet A-C, Young RN, Han Y, Heimark R et al (2007) The EP4 receptor antagonist, L-161982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells. Exp Cell Res 313:2969–2979. doi:10.1016/j.yexcr.2007.06.004

    PubMed  Article  CAS  Google Scholar 

  21. Kambe A, Iguchi G, Moon Y, Kamitani H, Watanabe T, Eling TE (2008) Regulation of EP4 expression via the Sp-1 transcription factor: inhibition of expression by anti-cancer agents. Biochim Biophys Acta 1783:1211–1219. doi:10.1016/j.bbamcr.2008.01.032

    PubMed  Article  CAS  Google Scholar 

  22. Mutoh MK, Watanabe T, Kitamura Y et al (2002) Involvement of prostaglandin E receptor subtype EP4 in colon carcinogenesis. Cancer Res 62:28–32

    PubMed  CAS  Google Scholar 

  23. Sonoshita M, Takaku K, Sasaki N et al (2001) Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc[Delta 716] knockout mice. Nat Med 9:1048–1051. doi:10.1038/nm0901-1048

    Article  Google Scholar 

  24. Watanabe K, Kawamori T, Nakatsugi S et al (1999) Role of the prostaglandin E receptor subtype EP1 in colon carcinogenesis. Cancer Res 59:5093–5096

    PubMed  CAS  Google Scholar 

  25. Kitamura T, Itoh M, Noda T et al (2003) Combined effects of prostaglandin E receptor subtype EP1 and subtype EP4 antagonists on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice. Cancer Sci 94:618–621. doi:10.1111/j.1349-7006.2003.tb01492.x

    PubMed  Article  CAS  Google Scholar 

  26. Tober KL, Wilgus TA, Kusewitt DF, Thomas-Ahner JM, Maruyama T, Oberyszyn TM (2006) Importance of the EP1 receptor in cutaneous UVB-induced inflammation and tumor development. J Invest Dermatol 126:205–211. doi:10.1038/sj.jid.5700014

    PubMed  Article  CAS  Google Scholar 

  27. Sung YM, He G, Fischer SM (2005) Lack of expression of the EP2 but not EP3 receptor for prostaglandin E2 results in suppression of skin tumor development. Cancer Res 65:9304–9311. doi:10.1158/0008-5472.CAN-05-1015

    PubMed  Article  CAS  Google Scholar 

  28. Konger RL, Scott GA, Landt Y, Ladenson JH, Pentland AP (2002) Loss of EP2 prostaglandin E2 receptor in immortalized human keratinocytes results in increased invasiveness and decreased paxillin expression. Am J Pathol 26:2065–2078

    Google Scholar 

  29. Chun K-S, Akunda JK, Langenbach R (2007) Cyclooxygenase-2 inhibits UVB-induced apoptosis in mouse skin by activating the prostaglandin E2 receptors, EP2 and EP4. Cancer Res 67:2015–2021. doi:10.1158/0008-5472.CAN-06-3617

    PubMed  Article  CAS  Google Scholar 

  30. Miyata Y, Kanda S, Nomata K, Eguchi J, Kanetake H (2005) Expression of cyclooxygenase-2 and EP4 receptor in transitional cell carcinoma of the upper urinary tract. J Urol 173:56–60

    PubMed  CAS  Google Scholar 

  31. Chell SD, Witherden IR, Dobson RR, Moorghen M, Herman AA, Qualtrough D et al (2006) Increased EP4 receptor expression in colorectal cancer progression promotes cell growth and anchorage independence. Cancer Res 66:3106–3113. doi:10.1158/0008-5472.CAN-05-3702

    PubMed  Article  CAS  Google Scholar 

  32. Gustafsson A, Hansson E, Kressner U, Nordgren S, Andersson M, Wang W et al (2007) EP1-4 subtype, COX and PPARγ receptor expression in colorectal cancer in prediction of disease-specific mortality. Int J Cancer 121:232. doi:10.1002/ijc.22582

    PubMed  Article  CAS  Google Scholar 

  33. Fulton AM, Laterra JJ, Hanchin CM (1989) Prostaglandin E2 receptor heterogeneity and dysfunction in mammary tumor cells. J Cell Physiol 139:93–99. doi:10.1002/jcp.1041390114

    PubMed  Article  CAS  Google Scholar 

  34. Fulton AM, Zhang S-Z, Chong YC (1991) Role of the prostaglandin E2 receptor in mammary tumor metastasis. Cancer Res 51:2047–2050

    PubMed  CAS  Google Scholar 

  35. Richards JA, Brueggemeier RW (2003) Prostaglandin E2 regulates aromatase activity and expression in human adipose stromal cells via two distinct receptor subtypes. J Clin Endocrinol Metab 88:2810–2816. doi:10.1210/jc.2002-021475

    PubMed  Article  CAS  Google Scholar 

  36. Subbaramaiah K, Hudis C, Chang S-H, Hla T, Dannenberg AJ (2008) EP2 and EP4 receptors regulate aromatase expression in human adipocytes and breast cancer cells. J Biol Chem 283:3433–3444. doi:10.1074/jbc.M705409200

    PubMed  Article  CAS  Google Scholar 

  37. Chang S-H, Liu CH, Conway R et al (2004) Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase-2-induced breast cancer progression. Proc Natl Acad Sci USA 101:591–596. doi:10.1073/pnas.2535911100

    PubMed  Article  CAS  Google Scholar 

  38. Kawamori T, Uchiya N, Nakatsugi S et al (2001) Chemopreventive effects of ONO-8711, a selective prostaglandin E receptor EP1 antagonist, on breast cancer development. Carcinogenesis 22:2001–2004. doi:10.1093/carcin/22.12.2001

    PubMed  Article  CAS  Google Scholar 

  39. Thorat MA, Morimiya A, Mehrotra S, Konger R, Badve S (2008) Prostanoid receptor EP1 expression in breast cancer. Mod Pathol 21:15–21. doi:10.1038/modpathol.3800970

    PubMed  Article  CAS  Google Scholar 

  40. Timoshenko AV, Xu G, Chakrabarti S, Lala PK, Chakraborty C (2003) Role of prostaglandin E2 receptors in migration of murine and human breast cancer cells. Exp Cell Res 289:265–274. doi:10.1016/S0014-4827(03)00269-6

    PubMed  Article  CAS  Google Scholar 

  41. Buchanan FG, Wang D, Bargiacchi F, DuBois RN (2003) Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 278:35451–35457. doi:10.1074/jbc.M302474200

    PubMed  Article  CAS  Google Scholar 

  42. Yang L, Huang Y, Porta R, Yanagisawa K, Gonzalex A, Segi E et al (2006) Host and direct antitumor effects and profound reduction in tumor metastasis with selective EP4 receptor antagonism. Cancer Res 66:9665–9672. doi:10.1158/0008-5472.CAN-06-1271

    PubMed  Article  CAS  Google Scholar 

  43. Pan M-R, Hou M-F, Chang H-C, Hung W-C (2008) Cyclooxygenase-2 upregulates CCR7 via EP2/EP4 receptor signaling pathways to enhance lymphatic invasion of breast cancer cells. J Biol Chem 283:11155–11163. doi:10.1074/jbc.M710038200

    PubMed  Article  CAS  Google Scholar 

  44. Chang S-H, Ai Y, Breyer RM, Lane TF, Hla T (2005) The prostaglandin E2 receptor EP2 is required for cyclooxygenase-2-mediated mammary hyperplasia. Cancer Res 65:4496–4499. doi:10.1158/0008-5472.CAN-05-0129

    PubMed  Article  CAS  Google Scholar 

  45. Narumiya S (2003) Prostanoids in immunity: roles revealed by mice deficient in their receptors. Life Sci 74:391–395. doi:10.1016/j.lfs.2003.09.025

    PubMed  Article  CAS  Google Scholar 

  46. Nataraj CD, Thomas W, Tilley SL, Nguyen M, Mannon R, Koller BH et al (2001) Receptors for prostaglandin E2 that regulate cellular immune responses in the mouse. J Clin Invest 108:1229–1235

    PubMed  CAS  Google Scholar 

  47. Yang LN, Yamagata R, Yadav S et al (2003) Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor. J Clin Invest 111:727–735

    PubMed  CAS  Google Scholar 

  48. Seno HM, Oshima T, Ishikawa H et al (2002) Cyclooxygenase 2 and prostaglandin E2 receptor EP2-dependent angiogenesis in Apcdelta716 mouse intestinal polyps. Cancer Res 62:506–511

    PubMed  CAS  Google Scholar 

  49. Amano HI, Hayashi H, Endo H et al (2003) Host prostaglandin E2-EP3 signaling regulates tumor-associated angiogenesis and tumor growth. J Exp Med 197:221–232. doi:10.1084/jem.20021408

    PubMed  Article  CAS  Google Scholar 

  50. Rao R, Redha R, Macias-Perez I, Su Y, Hao C, Zent R et al (2007) Prostaglandin E2-EP4 receptor promotes endothelial cell migration via ERK activation and angiogenesis in vivo. J Biol Chem 282:16959–16968. doi:10.1074/jbc.M701214200

    PubMed  Article  CAS  Google Scholar 

  51. George RJ, Sturmoski MA, Anant S, Houchen CW (2007) EP4 mediates PGE2 dependent cell survival through the PI3 Kinase/AKT pathway. Prostaglandins Other Lipid Mediat 83:112–120. doi:10.1016/j.prostaglandins.2006.10.005

    PubMed  Article  CAS  Google Scholar 

  52. Hawcroft G, Ko CWS, Hull MA (2007) Prostaglandin E2-EP4 receptor signaling promotes tumorigenic behaviour of HT-29 human colorectal cancer cells. Oncogene 26:3006–3019. doi:10.1038/sj.onc.1210113

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the United States Department of Defense and the Department of Health and Human Services. We thank the Biostatistics and Flow Cytometry Core Facilities of the University of Maryland Greenebaum Cancer Center.

Author information

Affiliations

  1. Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Namita Kundu, Xinrong Ma, Dawn Holt & Amy M. Fulton

  2. Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD, 21201, USA

    Olga Goloubeva & Amy M. Fulton

  3. Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD, 21250, USA

    Suzanne Ostrand-Rosenberg

Authors
  1. Namita Kundu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinrong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dawn Holt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Olga Goloubeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Suzanne Ostrand-Rosenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Amy M. Fulton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amy M. Fulton.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kundu, N., Ma, X., Holt, D. et al. Antagonism of the prostaglandin E receptor EP4 inhibits metastasis and enhances NK function. Breast Cancer Res Treat 117, 235–242 (2009). https://doi.org/10.1007/s10549-008-0180-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-008-0180-5

Keywords

  • Metastasis
  • COX-2
  • Prostaglandin EP receptors
  • Natural Killer cells