Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Tamoxifen regulates human telomerase reverse transcriptase (hTERT) gene expression differently in breast and endometrial cancer cells

Abstract

Tamoxifen is widely applied as an antiestrogenic agent for adjuvant therapy in the treatment of breast cancer, while its estrogen-agonistic activity occasionally causes proliferative disorders or carcinogenesis at other sites, such as the uterus. We reported that estrogen activates telomerase in breast and endometrial cancer cells. The present study examines the effects of tamoxifen on the gene expression of human telomerase reverse transcriptase (hTERT) in breast and endometrial cancer cells. Tamoxifen inhibited the cell growth of MCF-7 cells, as well as hTERT mRNA expression in the presence of estrogen (E2), antagonizing the E2 effects. In contrast, tamoxifen stimulated the growth of Ishikawa cells and activated hTERT mRNA expression in the absence or presence of E2, exhibiting estrogen-agonistic action. Transient expression assays revealed that these actions of tamoxifen are achieved by transcriptional regulation of the hTERT promoter. An estrogen responsive element (ERE) in the hTERT 5′ regulatory region was partly responsible for both the E2-antagonistic and -agonistic actions of tamoxifen. Tamoxifen activated the MAP kinase cascade in Ishikawa cells, but not in MCF-7 cells, and the activation of hTERT mRNA expression was effectively blocked by MEK inhibitor, suggesting that the MAP kinase pathway is involved in the tamoxifen-induced activation of hTERT. These findings indicate that tamoxifen regulates hTERT expression in a cell-type specific manner. Tamoxifen-induced activation of hTERT may be one component of estrogen agonistic function of tamoxifen that is involved in endometrial carcinogenesis induced by this agent.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  • Bergman L, Beelen ML, Gallee MP, Hollema H, Benraadt J, van Leeuwen FE . 2000 Lancet 356: 881–887

  • Berry M, Metzger D, Chambon P . 1990 EMBO J. 9: 2811–2818

  • Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE . 1998 Science 279: 349–352

  • Colacurci N, De Seta L, De Franciscis P, Mele D, Fortunato N, Cassese S . 2000 Panminerva. Med. 42: 45–47

  • Collins P, Webb C . 1999 Nat. Med. 5: 1130–1131

  • Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB, Bacchetti S . 1992 EMBO J. 11: 1921–1929

  • Endoh H, Sasaki H, Maruyama K, Takeyama K, Waga I, Shimizu T, Kato S, Kawashima H . 1997 Biochem. Biophys. Res. Commun. 235: 99–102

  • Fan JD, Wagner BL, McDonnell DP . 1996 Mol. Endocrinol. 10: 1605–1616

  • Goldstein SR . 2000 Eur. J. Cancer 36: Suppl 4 54–56

  • Hahn WC, Stewart SA, Brooks MW, York SG, Eaton E, Kurachi A, Beijersbergen RL, Knoll JH, Meyerson M, Weinberg RA . 1999 Nat. Med. 5: 1164–1170

  • Harley CB, Kim NW, Prowse KR, Weinrich SL, Hirsch KS, West MD, Bacchetti S, Hirte HW, Counter CM, Greider CW . 1994 Cold Spring Harb. Symp. Quant. Biol. 59: 307–315

  • Ito H, Kyo S, Kanaya T, Takakura M, Inoue M, Namiki M . 1998 Clin. Cancer Res. 4: 1603–1608

  • Jamil A, Croxtall JD, White JOJ . 1991 Mol. Endocrinol. 6: 215–221

  • Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H . 1995 Science 270: 1491–1494

  • Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW . 1994 Science 266: 2011–2015

  • Kyo S, Kanaya T, Takakura M, Tanaka M, Inoue M . 1999a Int. J. Cancer 80: 60–63

  • Kyo S, Takakura M, Kanaya T, Wang Z, Fujimoto K, Nishio Y, Orimo A, Inoue M . 1999b Cancer Res. 59: 5917–5921

  • Lasset C, Bonadona V, Mignotte H, Bremond A . 2001 Lancet 357: 66–67

  • Mandlekar S, Yu R, Tan TH, Kong AN . 2000 Cancer Res. 60: 5995–6000

  • Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, Nola E, Auricchio F . 1996 EMBO J. 15: 1292–1300

  • Mimnaugh EG, Chavany C, Neckers L . 1996 J. Biol. Chem. 271: 22796–22801

  • Nakayama J, Tahara H, Tahara E, Saito M, Ito K, Nakamura H, Nakanishi T, Ide T, Ishikawa F . 1998 Nat. Genet. 18: 65–68

  • Norris JD, Paige LA, Christensen DJ, Chang CY, Huacani MR, Fan D, Hamilton PT, Fowlkes DM, McDonnell DP . 1999 Science 285: 744–746

  • Rosenbaum Smith SM, Osborne MP . 2000 Am. J. Surg. 180: 249–251

  • Schwartzl B, Krey L, Demopoulos R, Goldstein SR, Nachtigall LE, Mittal K . 1997 Am. J. Obstet. Gynecol. 176: 129–137

  • Shay JW, Bacchetti S . 1997 Eur. J. Cancer 33: 787–791

  • Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL . 1998 Cell 95: 927–937

  • Singer CA, Figueroa-Masot XA, Batchelor RH, Dorsa DM . 1999 J. Neurosci. 19: 2455–2463

  • Soda H, Raymond E, Sharma S, Lawrence R, Davidson K, Oka M, Kohno S, Izbicka E, Von Hoff DD . 2000 Prostate 43: 161–168

  • Sundaresan S, Colin IM, Pestell RG, Jameson JL . 1996 Endocrinology 137: 304–311

  • Tora L, White J, Brou C, Tasset D, Webster N, Scheer E, Chambon P . 1989 Cell 59: 477–487

  • Tzukerman MT, Esty A, Santiso-Mere D, Danielan P, Parker MG, Stein RB, Pike JW, McDonnell DP . 1994 Mol. Endocrinol. 8: 21–30

  • Wang Z, Kyo S, Takakura M, Tanaka M, Yatabe N, Maida Y, Fujiwara M, Hayakawa J, Ohmichi M, Koike K, Inoue M . 2000 Cancer Res. 60: 5376–5381

  • Webb P, Lopez GN, Uht RM, Kushner P . 1995 J. Mol. Endocrinol. 9: 443–456

  • Weinstein SL, Gold MR, DeFranco AL . 1991 Proc. Natl. Acad. Sci. USA 88: 4148–4152

  • Zhang CC, Shapiro DJ . 2000 J. Biol. Chem. 275: 479–486

Download references

Acknowledgements

We are grateful to Dr Masato Nishida (Department of Obstetrics and Gynecology, Tsukuba University, Japan) for providing Ishikawa cells. This study was supported in part by a Grant-in-Aid for the Second Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health and Welfare as well as the Hokkoku Cancer Foundation, Japan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Satoru Kyo.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wang, Z., Kyo, S., Maida, Y. et al. Tamoxifen regulates human telomerase reverse transcriptase (hTERT) gene expression differently in breast and endometrial cancer cells. Oncogene 21, 3517–3524 (2002). https://doi.org/10.1038/sj.onc.1205463

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205463

Keywords

  • tamoxifen
  • telomerase
  • hTERT
  • endometrial cancer
  • breast cancer

Further reading

Search

Quick links