Skip to main content

Advertisement

SpringerLink
Log in

Estrogen receptor β potentiates the antiproliferative effect of raloxifene and affects the cell migration and invasion in HCT-116 colon cancer cells

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Estrogen receptor β (ERβ) is the predominant ER in the colorectal epithelium, whose expression is greatly reduced in colorectal cancer compared with normal colon tissue. Recent in vitro studies suggested that ERβ may suppress tumor growth. No research was reported whether ERβ can be used as therapeutic agent for colon cancer.

Methods

In this study, ERβ gene constructed into adenoviral (Ad) vectors was used to treat colon cancer HCT-116 cells alone or in combination with raloxifene. In vitro and in vivo studies were conducted to investigate the therapeutic effects of ERβ and raloxifene in HCT-116 cells.

Results

Our results indicated that, although Ad-ERβ alone had no effect on the proliferation of HCT-116 cells, the combination of Ad-ERβ with raloxifene significantly inhibited the proliferation of HCT-116 cells. The apparently apoptotic induction effects may partly explain the cytotoxicity of the two agents. The results of the study of ERβ on migration and invasion of HCT-116 cells demonstrated that overexpression of ERβ significantly decreased cell migration and increased invasion of cells. The antitumor efficacies of ERβ as well as raloxifene were further investigated on HCT-116 tumor bearing mice. Results demonstrated that both Ad-ERβ and raloxifene individually inhibited tumor growth. The combination group showed the highest inhibitory efficiency compared with other three groups.

Conclusion

These findings demonstrated that combined administration of Ad-ERβ with raloxifene represents a promising colon cancer therapeutic strategy.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P (2004) Loss of ERβ expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer 11:537–551

    Article  PubMed  CAS  Google Scholar 

  • Brossard D, Kihe LE, Clément M, Sebbahi W, Khalid M, Roussakis C, Rault S (2010) Synthesis of bile acid derivatives and in vitro cytotoxic activity with pro-apoptotic process on multiple myeloma (KMS-11), glioblastoma multiforme (GBM), and colonic carcinoma (HCT-116) human cell lines. Eur J Med Chem 45:2912–2918

    Article  PubMed  CAS  Google Scholar 

  • Bryant HU, Glasebrook AL, Yang NN, Sato M (1999) An estrogen receptor basis for raloxifene action in bone. J Steroid Biochem Mol Biol 69:37–44

    Article  PubMed  CAS  Google Scholar 

  • Campbell-Thompson M, Lynch IJ, Bhardwaj B (2001) Expression of estrogen receptor (ER) subtypes and ERβ isoforms in colon cancer. Cancer Res 61:632–640

    PubMed  CAS  Google Scholar 

  • Castiglione F, Taddei A, Degl’innocenti DR, Buccoliero AM, Bechi P, Garbini F, Gheri CF, Moncini D, Cavallina G, Marascio L, Freschi G, Taddei GL (2008) Expression of estrogen receptors [beta] in colon cancer progression. Diagn Mol Pathol 17:231–236

    Article  PubMed  CAS  Google Scholar 

  • Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC (1999) The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation (MORE). JAMA 281:2189–2197

    Article  PubMed  CAS  Google Scholar 

  • Deng H, Makizumi R, Ravikumar TS, Dong H, Yang W, Yang WL (2007) Bone morphogenetic protein-4 is overexpressed in colonic adenocarcinomas and promotes migration and invasion of HCT-116 cells. Exp Cell Res 313:1033–1044

    Article  PubMed  CAS  Google Scholar 

  • Edvardsson K, Ström A, Jonsson P, Gustafsson JÅ, Williams C (2011) Estrogen receptor beta induces antiinflammatory and antitumorigenic networks in colon cancer cells. Mol Endocrinol 25:1–11

    Article  Google Scholar 

  • Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Gluer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) investigators. JAMA 282:637–645

    Article  PubMed  CAS  Google Scholar 

  • Foley EF, Jazaeri AA, Shupnik MA, Jazaeri O, Rice LW (2000) Selective loss of estrogen receptor β in malignant human colon. Cancer Res 60:245–248

    PubMed  CAS  Google Scholar 

  • Grodstein F, Newcomb PA, Stampfer MJ (1999) Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 106:574–582

    Article  PubMed  CAS  Google Scholar 

  • Hartman J, Edvardsson K, Lindberg K, Zhao C, Williams C, Ström A, Gustafsson JA (2009) Tumor repressive functions of estrogen receptor beta in SW480 colon cancer cells. Cancer Res 69:6100–6106

    Article  PubMed  CAS  Google Scholar 

  • Hsu HH, Cheng SF, Wu CC, Chu CH, Weng YJ, Lin CS, Lee SD, Wu HC, Huang CY, Kuo WW (2006) Apoptotic effects of overexpressed estrogen receptor-beta on LoVo colon cancer cell is mediated by p53 signalings in a ligand-dependent manner. Chin J Physiol 49:110–116

    PubMed  CAS  Google Scholar 

  • Janakiram NB, Steele VE, Rao CV (2009) Estrogen receptor-β as a potential target for colon cancer prevention: chemoprevention of azoxymethane-induced colon carcinogenesis by raloxifene in F344 rats. Cancer Prev Res 2:52–59

    Article  CAS  Google Scholar 

  • Jassam N, Bell SM, Speirs V, Quirke P (2005) Loss of expression of oestrogen receptor β in colon cancer and its association with Dukes’ staging. Oncol Rep 14:17–21

    PubMed  CAS  Google Scholar 

  • Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics. CA Cancer J Clin 58:71–96

    Article  PubMed  Google Scholar 

  • Jooss K, Chirmule N (2003) Immunity to adenovirus and adeno-associated viral vectors: Implications for gene therapy. Gene Ther 10:955–963

    Article  PubMed  CAS  Google Scholar 

  • Katznellenbogen BS, Katznellenbogen JA (2002) Defining the “S” in SERMs. Science 295:2380–2381

    Article  Google Scholar 

  • Konstantinopoulos PA, Kominea A, Vandoros G, Sykiotis GP, Andricopoulos P, Varakis I, Sotiropoulou-Bonikou G, Papavassiliou AG (2003) Oestrogen receptor beta (ERβ) is abundantly expressed in normal colonic mucosa, but declines in colon adenocarcinoma paralleling the tumour’s dedifferentiation. Eur J Cancer 39:1251–1258

    Article  PubMed  CAS  Google Scholar 

  • Kuiper GGJM, Lemmen JG, Carlsson B (1998) Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor-β. Endocrinology 3:4252–4263

    Article  Google Scholar 

  • Lee DE, Lee KW, Jung SK, Lee EJ, Hwang JA, Lim TG, Kim BY, Bode AM, Lee HJ, Dong Z (2011) 6,7,4′-Trihydroxyisoflavone inhibits HCT-116 human colon cancer cell proliferation by targeting CDK1 and CDK2. Carcinogenesis 32:629–635

    Article  PubMed  CAS  Google Scholar 

  • Levy N, Tatomer D, Herber CB, Zhao X, Tang H, Sargeant T, Ball LJ, Summers J, Speed TP, Leitman DC (2008) Differential regulation of native estrogen receptor-regulatory elements by estrodiol, tamoxifen, and raloxifene. Mol Endocrinol 22:287–303

    Article  PubMed  CAS  Google Scholar 

  • Martineti V, Picariello L, Tognarini I, Sala SC, Gozzini A, Azzari C, Mavilia C, Tanini A, Falchetti A, Fiorelli G, Tonelli F, Brandi ML (2005) ERβ is a potent inhibitor of cell proliferation in the HCT8 human colon cancer cell line through regulation of cell cycle components. Endocr Relat Cancer 12:455–469

    Article  PubMed  CAS  Google Scholar 

  • Mayo Clinic Women’s HealthSource (2006) Raloxifene works as well as tamoxifen in preventing invasive breast cancer. Mayo Clin Women’s HealthSource 10:3

    Google Scholar 

  • Morishima S, Shibata MA, Ohmichi M, Otsuki Y (2008) Raloxifene, a selective estrogen receptor modulator, induces mitochondria-mediated apoptosis in human endometrial carcinoma cells. Med Mol Morphol 4:132–138

    Article  Google Scholar 

  • Motylewska E, Stasikowska O, Mełeń-Mucha G (2009) The inhibitory effect of diarylpropionitrile, a selective agonist of estrogen receptor beta, on the growth of MC38 colon cancer line. Cancer Lett 276:68–73

    Article  PubMed  CAS  Google Scholar 

  • Ning T, Yan X, Lu ZJ, Wang GP, Zhang NG, Yang JL, Jiang SS, Wu Y, Yang L, Guan YS, Luo F (2009) Gene therapy with the angiogenesis inhibitor endostatin in an orthotopic lung cancer murine model. Hum Gene Ther 20:103–111

    Article  PubMed  CAS  Google Scholar 

  • Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108

    Article  PubMed  Google Scholar 

  • Parmar H, Young P, Emerman JT, Neve RM, Dairkee S, Cunha GR (2002) A novel method for growing human breast epithelium in vivo using mouse and human mammary fibroblasts. Endocrinology 143:4886–4896

    Article  PubMed  CAS  Google Scholar 

  • Paruthiyil S, Parmar H, Kerekatte V, Cunha GR, Firestone GL, Leitman DC (2004) Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res 64:423–428

    Article  PubMed  CAS  Google Scholar 

  • Pasi AJ, Robert JM (2000) Chemoprevention of colorectal cancer. New Engl J Med 342:1960–1968

    Article  Google Scholar 

  • Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled trial. JAMA 288:321–333

    Article  PubMed  CAS  Google Scholar 

  • Sasaki K, Tsuno NH, Sunami E, Tsurita G, Kawai K, Okaji Y, Nishikawa T, Shuno Y, Hongo K, Hiyoshi M, Kaneko M, Kitayama J, Takahashi K, Nagawa H (2010) Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells. BMC Cancer 10:370

    Article  PubMed  Google Scholar 

  • Schrag D (2004) The price tag on progress-chemotherapy for colorectal cancer. N Engl J Med 351:317–319

    Article  PubMed  CAS  Google Scholar 

  • Terranova VP, Hujanen ES, Loeb DM, Martin GR, Thornburg L, Glushko V (1986) Use of a reconstituted basement membrane to measure cell invasiveness and select for highly invasive tumor cells. Proc Natl Acad Sci USA 83:465–469

    Article  PubMed  CAS  Google Scholar 

  • Waliszewski P, Blaszczyk M, Wolinska-Witort E, Drews M, Snochowski M, Hurst RE (1997) Molecular study of sex steroid receptor gene expression in human colon and in colorectal carcinomas. J Surg Oncol 64:3–11

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Wang Q, Ives KL, Evers BM (2006) Curcumin inhibits neurotensin-mediated interleukin-8 production and migration of HCT116 human colon cancer cells. Clin Cancer Res 12:5346–5355

    Article  PubMed  CAS  Google Scholar 

  • Wickerham DL, Costantino JP, Vogel VG, Cronin WM, Cecchini RS, Ford LG, Wolmark N (2009) The use of tamoxifen and raloxifene for the prevention of breast cancer. Recent Results Cancer Res 181:113–119

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Guowei Gu (Calabria, Italy) for the gift of Plasmid pCMV5-hERβ. We are also grateful to Professor Tao Xi (Nanjing, China) for the supports during this study. This research was supported by the Natural Science Foundation Committee of China (NSFC 30672015, 30700779, 30800257, 30970776, 81000666, 81071194, 31050110123, 81171395) and the major project from the Ministry of Science and Technology for new drug development (2009ZX09310-004).

Conflict of interest

The authors have no conflicts to disclose.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China

    Zhenzhen Tu, Yuxiang Ma, Junmei Tian, Hui Li & Yueqing Gu

  2. Department of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA

    Walter Akers & Samuel Achilefu

Authors
  1. Zhenzhen Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuxiang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junmei Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Walter Akers
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Samuel Achilefu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yueqing Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yueqing Gu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tu, Z., Ma, Y., Tian, J. et al. Estrogen receptor β potentiates the antiproliferative effect of raloxifene and affects the cell migration and invasion in HCT-116 colon cancer cells. J Cancer Res Clin Oncol 138, 1091–1103 (2012). https://doi.org/10.1007/s00432-011-1145-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-011-1145-3

Keywords

Search

Navigation