Comparison and Analysis between Human Breast Cancer Cells and Hepatoma Cells for the Effects of Xenobiotic Nuclear Receptors (Constitutive Androstane Receptor, Steroid and Xenobiotic Receptor, and Peroxisome-Proliferator-Activated Receptor γ ) on the Transcriptional Activity of Estrogen Receptor

유방암 세포와 간암세포에 있어서 에스트로겐 수용체의 전사조절기능에 대한 Xenobiotic 핵 수용체 (Constitutive Androstane Receptor, Steroid and Xenobiotic Receptor, Peroxisome-Proliferator-Activated Receptor γ )의 영향 비교분석

  • 민계식 (진주산업대학교 미생물공학과)
  • Published : 2003.06.01


The purpose of this study was to examine the effects of xenobiotic nuclear receptors, CAR, SXR, and PPAR${\gamma}$ on the transcriptional activity of estrogen receptor in human breast cancer cell lines and compare with those in human hepatoma cell line. Two different breast cancer cell lines, MCF-7 and MDA-MB-231 were cultured and effects of CAR, SXR, and PPAR${\gamma}$ on the ER-mediated transcriptional activation of synthetic (4ERE)-tk-luciferase reporter gene were analyzed. Consistent with the previous report, CAR significantly inhibited ER-mediated transactivation and SXR repressed modestly whereas the PPAR${\gamma}$ did not repress the ER-mediated transactivation. However, in breast cancer cells neither of the xenobiotic receptors repressed the ER-mediated transactivation. Instead, they tend to increase the transactivation depending on the cell type and xenobiotic nuclear receptors. In MCF-7, SXR but neither CAR nor PPAR${\gamma}$ slightly increased ER-mediated transactivation whereas in MDA-MB-231, CAR and PPAR${\gamma}$ but not SXR tend to increase the transactivation of the reporter gene. These results indicate that the effects of ER cross-talk by the CAR, SXR, and PPAR${\gamma}$ , are different in breast cancer cells from hepatoma cells. In conclusion, the transcriptional regulation by estrogen can involve different cross-talk interaction between estrogen receptor and xenobiotic nuclear receptors depending on the estrogen target cells.


  1. Blumberg, B. and R.M. Evans. 1998. Orphan nuclear receptors-new ligands and new possibilities. Genes Dev. 15, 3149-3155
  2. Blumberg, B., W. Jr. Sabbagh, H. Juguilon, J. Jr. Bolado, CM. van. Meter, E. S. Ong and R M. Evans. 1998. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Oev. 15, 3195-3205
  3. Clay, C. E., A. M. Namen, G. Atsumi, M. C. Willingham, K. P. High, T. E. Kute, A. J. Trimboli, A. N. Fonteh, P. A. Dawson and F. H. Chilton. 1999. Influence of J series prostaglandins on apoptosis and tumorigenesis of breast cancer cells. Carcinogenesis. 20, 1905-1911
  4. Duan, R., W. Porter, I. Samudio, C. Vyhlida!, M. Kladde and S. Safe. 1999. Transcriptional activation of c-fos protooncogene by 17beta-estradiol: mech-anism of aryl hydrocarbon receptor-mediated inhi-bition. Mol. Endocrinol. 13, 1511-1521
  5. Elstner, E., C. Muller, K. Koshizuka, E. A. Williamson, D. Park, H. Asou, P. Shintaku, J. W. Said. D. Heber and H. P. Koeffler. 1998. Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc. Natl. Acad. Sci. 21, 8806-8811
  6. Forman, B. M., I. Tzameli, H. S. Choi, J. Chen, D. Sirnha, W. Seol, R M. Evans and D. D. Moore. 1998. Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature. 8, 612-615
  7. Glass, C. K., J. M. Holloway, O. V. Devary and M. G. Rosenfeld. 1988. The thyroid hormone receptor binds with opposite transcriptional effects to a common sequence motif in thyroid hormone and es-trogen response elements. Cell. 29, 313-323
  8. Katzenellenbogen, B. S. and J. A Katzenellenbogen. 2000. Estrogen receptor transcription and trans-activation: Estrogen receptor alpha and estrogen receptor beta: regulation by selective estrogen receptor modulators and importance in breast cancer. Breast Cancer Res. 2, 335-344
  9. Keller, H., F. Givel, M. Perroud and W. Wahli. 1995. Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements. Mol. Endocrinol. 9, 794-804
  10. Kharat, I. and F. Saatcioglu. 1996. Antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin are medi-ated by direct transcriptional interference with the liganded estrogen receptor. Cross-talk between aryl hydrocarbon- and estrogen-mediated signaling. J. BioI. Chem. 3, 10533-10537
  11. Kliewer, S. A, J. M. Lehmann and T. M. Willson. 1999. Orphan nuclear receptors: shifting endocrinology into reverse. Science. 30, 757-760
  12. Kraus, W. L., K. E. Weis and B. S. Katzenellenbogen. 1995. Inhibitory cross-talk between steroid hormone receptors: differential targeting of estrogen receptor in the repression of its transcriptional activity by agonist-and antagonist-occupied progestin receptors. Mol. Cell BioI. 15, 1847-1857
  13. McKay, L. I. and J. A. Cidlowski. 1998. Cross-talk between nuclear factor-kappa B and the steroid hormone receptors: mechanisms of mutual antago-nism. Mol. Endocrinol. 12, 45-56
  14. Menck, H. R, J. M. Jessup, H. J. Eyre, M. P. Cunningham, A. Fremgen, G. P. Murphy and D. P. Winchester. 1997. Clinical highlights from the National Cancer Data Base. CA. Cancer J- Clin. 47, 161-170
  15. Min, G., J. K. Kemper and B. Kemper. 2002. Glucocorticoid receptor-interacting protein 1 mediates ligand-independent nuclear translocation and activation of constitutive androstane receptor in vivo. J. BioI. Chem. 277, 26356-26363
  16. Min, G., H. Kim, Y. Bae, L. Petz and J. K Kemper. 2002. Inhibitory cross-talk between estrogen receptor (ER) and constitutively activated androstane receptor (CAR). CAR inhibits ER-mediated signaling pathway by squelching p160 coactivators. J. BioI. Chem. 13, 34626-34633
  17. Moore, L. B., D. J. Parks, S, A. Jones, R. K. Bledsoe, T. G. Consler, J. B. Stimmel, B. Goodwin, C. Liddle, S. G. Blanchard, T. M. Willson, J. L. Collins and S.A. Kliewer. 2000. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J. BioI. Chem. 19, 15122-15127
  18. Nunez, S. B., J. A. Medin, O. Braissant, L. Kemp, W. Wahli, K Ozato and J. H. Segars. 1997. Retinoid X receptor and peroxisome proliferator-activated rece-ptor activate an estrogen responsive gene independent of the estrogen receptor. Mol. Cell Endocrinol. 14, 27-40
  19. Paech, K, P. Webb, G. G. Kuiper, S. Nilsson, J. Gustafsson, P. J. Kushner and T. S. Scanlan. 1997. Differential ligand activation of estrogen receptors ERalpha and ERbeta at API sites. Science. 277, 1508-1510
  20. Ricci, M. S., D. G. Toscano, C. J. Mattingly and W. A. Jr. Toscano. 1999. Estrogen receptor reduces CYP1A1 induction in cultured human endometrial cells. J. BioI. Chem. 5, 3430-3438
  21. Seol, W., B. Hanstein, M. Brown and D. D. Moore.1998. Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner). Mol. Endocrinoi. 12, 1551-1557
  22. Smith C. L. 1998. Cross-talk between peptide growth factor and estrogen receptor signaling pathways. BioI. Reprod. 58, 627-632
  23. Sugatani, J., H. Kojima, A. Veda, S. Kakizaki, K Yoshinari, Q. H. Gong, I. S. Owens, M. Negishi and T. Sueyoshi. 2001. The phenobarbital response en-hancer module in the human bilirubin UDP-glucuronosyltransferase UGTlAl gene and regulation by the nuclear receptor CAR. Hepatology. 33, 1232-1238
  24. Tzameli, I., P. Pissios, E. G. Schuetz and D. D. Moore. 2000. The xenobiotic compound 1,4-bis[2-(3,5dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR. Mol. Cell BioI. 20, 2951-2958
  25. Wei. P., J. Zhang. M. Egan-Hafley, S. Liang and D. D. Moore. 2000. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature. 19, 920-923

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