Skip to main content

Advertisement

SpringerLink
Log in

Role of ornithine decarboxylase in regulation of estrogen receptor alpha expression and growth in human breast cancer cells

  • Preclinical Study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Our previous studies demonstrated that specific polyamine analogues, oligoamines, down-regulated the activity of a key polyamine biosynthesis enzyme, ornithine decarboxylase (ODC), and suppressed expression of estrogen receptor alpha (ERα) in human breast cancer cells. However, the mechanism underlying the potential regulation of ERα expression by polyamine metabolism has not been explored. Here, we demonstrated that RNAi-mediated knockdown of ODC (ODC KD) down-regulated the polyamine pool, and hindered growth in ERα-positive MCF7 and T47D and ERα-negative MDA-MB-231 breast cancer cells. ODC KD significantly induced the expression and activity of the key polyamine catabolism enzymes, spermine oxidase (SMO) and spermidine/spermine N 1-acetyltransferase (SSAT). However, ODC KD-induced growth inhibition could not be reversed by exogenous spermidine or overexpression of antizyme inhibitor (AZI), suggesting that regulation of ODC on cell proliferation may involve the signaling pathways independent of polyamine metabolism. In MCF7 and T47D cells, ODC KD, but not DFMO treatment, diminished the mRNA and protein expression of ERα. Overexpression of antizyme (AZ), an ODC inhibitory protein, suppressed ERα expression, suggesting that ODC plays an important role in regulation of ERα expression. Decrease of ERα expression by ODC siRNA altered the mRNA expression of a subset of ERα response genes. Our previous analysis showed that oligoamines disrupt the binding of Sp1 family members to an ERα minimal promoter element containing GC/CA-rich boxes. By using DNA affinity precipitation and mass spectrometry analysis, we identified ZBTB7A, MeCP2, PARP-1, AP2, and MAZ as co-factors of Sp1 family members that are associated with the ERα minimal promoter element. Taken together, these data provide insight into a novel antiestrogenic mechanism for polyamine biosynthesis enzymes in breast cancer.

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
Fig. 7

Similar content being viewed by others

References

  1. Porter CW, Herrera-Ornelas L, Pera P, Petrelli NF, Mittelman A (1987) Polyamine biosynthetic activity in normal and neoplastic human colorectal tissues. Cancer 60(6):1275–1281

    Article  PubMed  CAS  Google Scholar 

  2. LaMuraglia GM, Lacaine F, Malt RA (1986) High ornithine decarboxylase activity and polyamine levels in human colorectal neoplasia. Ann Surg 204(1):89–93

    Article  PubMed  CAS  Google Scholar 

  3. Manni A (2002) Polyamine involvement in breast cancer phenotype. In Vivo 16(6):493–500

    PubMed  CAS  Google Scholar 

  4. Manni A (1994) The role of polyamines in the hormonal control of breast cancer cell proliferation. Cancer Treat Res 71:209–225

    Article  PubMed  CAS  Google Scholar 

  5. Thomas T, Thomas TJ (1994) Estradiol control of ornithine decarboxylase mRNA, enzyme activity, and polyamine levels in MCF-7 breast cancer cells: therapeutic implications. Breast Cancer Res Treat 29(2):189–201

    Article  PubMed  CAS  Google Scholar 

  6. Cohen FJ, Manni A, Glikman P, Bartholomew M, Demers L (1988) Involvement of the polyamine pathway in antiestrogen-induced growth inhibition of human breast cancer. Cancer Res 48(23):6819–6825

    PubMed  CAS  Google Scholar 

  7. Nemoto T, Hori H, Yoshimoto M, Seyama Y, Kubota S (2002) Overexpression of ornithine decarboxylase enhances endothelial proliferation by suppressing endostatin expression. Blood 99(4):1478–1481

    Article  PubMed  CAS  Google Scholar 

  8. Huang Y, Hager ER, Phillips DL, Dunn VR, Hacker A, Frydman B, Kink JA, Valasinas AL, Reddy VK, Marton LJ et al (2003) A novel polyamine analog inhibits growth and induces apoptosis in human breast cancer cells. Clin Cancer Res 9(7):2769–2777

    PubMed  CAS  Google Scholar 

  9. Huang Y, Keen JC, Pledgie A, Marton LJ, Zhu T, Sukumar S, Park BH, Blair B, Brenner K, Casero RA Jr et al (2006) Polyamine analogues down-regulate estrogen receptor alpha expression in human breast cancer cells. J Biol Chem 281(28):19055–19063

    Article  PubMed  CAS  Google Scholar 

  10. Bergeron RJ, Neims AH, McManis JS, Hawthorne TR, Vinson JR, Bortell R, Ingeno MJ (1988) Synthetic polyamine analogues as antineoplastics. J Med Chem 31(6):1183–1190

    Article  PubMed  CAS  Google Scholar 

  11. Seely JE, Pegg AE (1983) Ornithine decarboxylase (mouse kidney). Methods Enzymol 94:158–161

    Article  PubMed  CAS  Google Scholar 

  12. Wang Y, Devereux W, Woster PM, Stewart TM, Hacker A, Casero RA Jr (2001) Cloning and characterization of a human polyamine oxidase that is inducible by polyamine analogue exposure. Cancer Res 61(14):5370–5373

    PubMed  CAS  Google Scholar 

  13. Huang Y, Stewart TM, Wu Y, Baylin SB, Marton LJ, Perkins B, Jones RJ, Woster PM, Casero RA Jr (2009) Novel oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes. Clin Cancer Res 15(23):7217–7228

    Article  PubMed  CAS  Google Scholar 

  14. Mitchell JL, Leyser A, Holtorff MS, Bates JS, Frydman B, Valasinas AL, Reddy VK, Marton LJ (2002) Antizyme induction by polyamine analogues as a factor of cell growth inhibition. Biochem J 366(Pt 2):663–671

    Article  PubMed  CAS  Google Scholar 

  15. Mitchell JL, Simkus CL, Thane TK, Tokarz P, Bonar MM, Frydman B, Valasinas AL, Reddy VK, Marton LJ (2004) Antizyme induction mediates feedback limitation of the incorporation of specific polyamine analogues in tissue culture. Biochem J 384(Pt 2):271–279

    PubMed  CAS  Google Scholar 

  16. Murai N, Murakami Y, Matsufuji S (2003) Identification of nuclear export signals in antizyme-1. J Biol Chem 278(45):44791–44798

    Article  PubMed  CAS  Google Scholar 

  17. Newman RM, Mobascher A, Mangold U, Koike C, Diah S, Schmidt M, Finley D, Zetter BR (2004) Antizyme targets cyclin D1 for degradation. A novel mechanism for cell growth repression. J Biol Chem 279(40):41504–41511

    Article  PubMed  CAS  Google Scholar 

  18. Huang Y, Keen JC, Hager E, Smith R, Hacker A, Frydman B, Valasinas AL, Reddy VK, Marton LJ, Casero RA Jr et al (2004) Regulation of polyamine analogue cytotoxicity by c-Jun in human MDA-MB-435 cancer cells. Mol Cancer Res 2(2):81–88

    PubMed  CAS  Google Scholar 

  19. Huang Y, Pledgie A, Rubin E, Marton LJ, Woster PM, Sukumar S, Casero RA Jr, Davidson NE (2005) Role of p53/p21(Waf1/Cip1) in the regulation of polyamine analogue-induced growth inhibition and cell death in human breast cancer cells. Cancer Biol Ther 4(9):1006–1013

    Article  PubMed  CAS  Google Scholar 

  20. Huang Y, Pledgie A, Casero R Jr, Davidson N (2005) Molecular mechanisms of polyamine analogs in cancer cells. Anticancer Drugs 16(3):229–241

    Google Scholar 

  21. Zu X, Yu L, Sun Q, Liu F, Wang J, Xie Z, Wang Y, Xu W, Jiang Y (2009) SP1 enhances Zbtb7A gene expression via direct binding to GC box in HePG2 cells. BMC Res Notes 2:175

    Article  PubMed  Google Scholar 

  22. Choi WI, Jeon BN, Park H, Yoo JY, Kim YS, Koh DI, Kim MH, Kim YR, Lee CE, Kim KS et al (2008) Proto-oncogene FBI-1 (Pokemon) and SREBP-1 synergistically activate transcription of fatty-acid synthase gene (FASN). J Biol Chem 283(43):29341–29354

    Article  PubMed  CAS  Google Scholar 

  23. Lee DK, Kang JE, Park HJ, Kim MH, Yim TH, Kim JM, Heo MK, Kim KY, Kwon HJ, Hur MW (2005) FBI-1 enhances transcription of the nuclear factor-kappaB (NF-kappaB)-responsive E-selectin gene by nuclear localization of the p65 subunit of NF-kappaB. J Biol Chem 280(30):27783–27791

    Article  PubMed  CAS  Google Scholar 

  24. Qu H, Qu D, Chen F, Zhang Z, Liu B, Liu H (2010) ZBTB7 overexpression contributes to malignancy in breast cancer. Cancer Invest 28(6):672–678

    Article  PubMed  CAS  Google Scholar 

  25. Wilson ME, Westberry JM (2009) Regulation of oestrogen receptor gene expression: new insights and novel mechanisms. J Neuroendocrinol 21(4):238–242

    Article  PubMed  CAS  Google Scholar 

  26. Westberry JM, Trout AL, Wilson ME (2009) Epigenetic regulation of estrogen receptor alpha gene expression in the mouse cortex during early postnatal development. Endocrinology 151(2):731–740

    Article  PubMed  Google Scholar 

  27. Sharma D, Blum J, Yang X, Beaulieu N, Macleod AR, Davidson NE (2005) Release of methyl CpG binding proteins and histone deacetylase 1 from the estrogen receptor alpha (ER) promoter upon reactivation in ER-negative human breast cancer cells. Mol Endocrinol 19(7):1740–1751

    Article  PubMed  CAS  Google Scholar 

  28. Frizzell KM, Kraus WL (2009) PARP inhibitors and the treatment of breast cancer: beyond BRCA1/2? Breast Cancer Res 11(6):111

    Article  PubMed  Google Scholar 

  29. Babbar N, Gerner EW (2011) Targeting polyamines and inflammation for cancer prevention. Recent Results Cancer Res 188:49–64

    Article  PubMed  Google Scholar 

  30. Mamont PS, Duchesne MC, Grove J, Bey P (1978) Anti-proliferative properties of dl-alpha-difluoromethyl ornithine in cultured cells. A consequence of the irreversible inhibition of ornithine decarboxylase. Biochem Biophys Res Commun 81(1):58–66

    Article  PubMed  CAS  Google Scholar 

  31. Abeloff MD, Rosen ST, Luk GD, Baylin SB, Zeltzman M, Sjoerdsma A (1986) Phase II trials of alpha-difluoromethylornithine, an inhibitor of polyamine synthesis, in advanced small cell lung cancer and colon cancer. Cancer Treat Rep 70(7):843–845

    PubMed  CAS  Google Scholar 

  32. Alhonen-Hongisto L, Poso H, Janne J (1980) Inhibition by derivatives of diguanidines of cell proliferation in Ehrlich ascites cells grown in cultures. Biochem J 188(2):491–501

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was funded by NIH Grants CA 51085 and CA 98454, the Breast Cancer Research Foundation, Susan G. Komen Foundation and the Samuel and Emma Winters Foundation.

Conflict of interest

The authors declare that there are no conflicts of interest.

Author information

Authors and Affiliations

  1. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    Qingsong Zhu, Lihua Jin & Robert A. Casero

  2. Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Nancy E. Davidson & Yi Huang

  3. University of Pittsburgh Cancer Institute, 5150 Centre Avenue Suite 500, Pittsburgh, PA, 15213, USA

    Nancy E. Davidson & Yi Huang

Authors
  1. Qingsong Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lihua Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert A. Casero
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nancy E. Davidson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Nancy E. Davidson or Yi Huang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhu, Q., Jin, L., Casero, R.A. et al. Role of ornithine decarboxylase in regulation of estrogen receptor alpha expression and growth in human breast cancer cells. Breast Cancer Res Treat 136, 57–66 (2012). https://doi.org/10.1007/s10549-012-2235-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-012-2235-x

Keywords

Search

Navigation