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.

  • Original Paper
  • Published:

Chemoprevention of mammary carcinogenesis in a transgenic mouse model by α-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity

Oncogene volume 22, pages 2568–2572 (2003)Cite this article

Abstract

Mechanisms underlying the chemopreventive effect of difluoromethylornithine (DFMO) on the development of mammary cancer were investigated utilizing the whey acidic protein promoter-T antigen transgenic mouse model of breast cancer progression. Mice were exposed to four different doses of DFMO in the diet (3.5, 4.9, 7.0 and 10 g/kg diet). Tumor latency was increased in a dose-dependent manner. DFMO at the highest dose significantly delayed tumor onset (131 days as compared to 109 days in control unexposed mice, P=0.018). Analyses of preneoplastic mammary tissue collected 1 month after DFMO treatment demonstrated that DFMO (10 g/kg diet) significantly increased the ratio of apoptotic to proliferative indices (P=0.013) and significantly reduced the percentage of cells demonstrating nuclear localized cyclin D1 (P=0.013). Nuclear localizations of p27, p21 and Stat5a were not affected. Inhibitory effects of DFMO on cell growth and survival were lost as the cells progressed to cancer. In conclusion, the chemopreventive effects of DFMO on mammary cancer progression were mediated by changes in both apoptosis and cell proliferation in preneoplastic cells. Alterations in cyclin D1 activity in preneoplastic cells could represent an early biomarker of chemopreventive action and are consistent with a mechanistic role for cyclin D1 in progression of mammary cancer.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Alt JR, Gladden AB and Diehl JA . (2002). J. Biol. Chem., 277, 8517–8523.

  • Arbeit JM, Riley RR, Huey B, Porter C, Kelloff G, Lubet R, Ward JM and Pinkel D . (1999). Cancer Res., 59, 3610–3620.

  • Baldin V, Lukas J, Marcote MJ, Pagano M and Draetta G . (1993). Genes Dev., 7, 812–821.

  • Cooper RL, Goldman JM and Vandenbergh JG . (1993). Methods in Toxicology, Vol. 3B. Heindel JJ, Chapin RE (eds), Academic Press: San Diego, pp. 45–56.

    Google Scholar 

  • Diehl JA, Cheng M, Roussel MF and Sherr CJ . (1998). Genes Dev., 12, 3499–3511.

  • Fozard JR, Part ML, Prakash NJ and Grove J . (1980). Eur. J. Pharmacol., 65, 379–391.

  • Furth PA . (1998). Dev. Biol. Stand., 94, 281–287.

  • Furth PA, Bar-Peled U, Li M, Lewis A, Laucirica R, Jager R, Weiher H and Russell RG . (1999). Oncogene, 18, 6589–6596.

  • Green JE, Shibata MA, Shibata E, Moon RC, Anver MR, Kelloff G and Lubet R . (2001). Cancer Res., 61, 7449–7455.

  • Gupta S, Afaq F and Mukhtar H . (2002). Oncogene, 21, 3727–3738.

  • Hursting SD, Perkins SN, Phang JM and Barrett JC . (2001). J. Nutr., 131, 3092S–3094S.

  • Ioachim EE, Malamou-Mitsi V, Kamina SA, Goussia AC and Agnantis NJ . (2000). Anticancer Res., 20, 4221–4225.

  • Joe AK, Liu H, Suzui M, Vural ME, Xiao D and Weinstein IB . (2002). Clin. Cancer Res., 8, 893–903.

  • Kelloff CJ, Lubet RA, Lieberman R, Eisenhauser K, Steele VE, Crowell JA, Hawk ET, Boone CW and Sigman C . (1998). Cancer Epidem. Biomarkers Prevention, 7, 65–78.

  • Kingsnorth AN, Russell WE, McCann PP, Diekema KA and Malt RA . (1983). Cancer Res., 43, 4035–4038.

  • Li M, Hu J, Heermeier K, Hennighausen L and Furth PA . (1996). Cell Growth Diff., 7, 3–11.

  • Li M, Lewis B, Capuco A, Laucirca R and Furth PA . (2000). Oncogene, 19, 1010–1019.

  • Masuda M, Toh S, Koike K, Kuratomi Y, Suzui M, Deguchi A, Komiyama S and Weinstein IB . (2002). Jpn. J. Cancer Res., 93, 329–339.

  • Nandi S, Guzman RC and Yang J . (1995). Proc. Natl. Acad. Sci. USA, 92, 3650–3657.

  • Pegg AE, McGovern KA and Wiest L . (1987). Biochem. J., 241, 305–307.

  • Peralta Soler A, Gilliard G, Megosh L, George K and O'Brien TG . (1998). Cancer Res., 58, 1654–1659.

  • Pidgeon GP, Kandouz M, Meram A and Honn KV . (2002). Cancer Res., 62, 2721–2727.

  • Ratko TA, Detrisac CJ, Rao KV, Thomas CF, Kelloff GJ and Moon RC . (1990). Anticancer Res., 10, 67–72.

  • Reddy BS, Nayini J, Tokumo K, Rigotty S, Zang E and Kelloff G . (1990). Cancer Res., 50, 2562–2568.

  • Reddy PR and Rukmini V . (1981). Contraception, 24, 215–221.

  • Ren S, Li M, Cai H, Hudgins S and Furth PA . (2000). Contemp. Top. Lab. Animal Sci., 40, 27–30.

  • Ren S, Cai HR, Li M and Furth PA . (2002). Oncogene, 21, 4335–4339.

  • Russo IH and Russo J . (1996). Health Perspect., 104, 938–967.

  • Seufferlein T, Seckl MJ, Schwarz E, Beil M, van Wichert G, Baust H, Luhrs H, Schmid RM and Adler G . (2002). Br. J. Cancer, 86, 1188–1196.

  • Thompson HJ and Ronan AM . (1986). Carcinogenesis, 7, 2003–2006.

  • Tzeng YJ, Guhl E, Graessmann M and Graessmann A . (1993). Oncogene, 8, 1965–1971.

  • Yoshidome K, Shibata M-A, Couldrey C, Korach KS and Green JE . (2000). Cancer Res., 60, 6901–6910.

  • Zhai S, Senderowicz AM, Sausville EA and Figg WD . (2002). Ann. Pharmacother., 36, 905–911.

  • Zhang M, Shi Y, Magit D, Furth PA and Sager R . (2000). Oncogene, 19, 6053–6058.

Download references

Acknowledgements

Supported by NIH, NCI, MAO/RFP NO1-CN-85076-46 (CJG and PAF) and NIH HD 38955 (JAF).

Author information

Authors and Affiliations

  1. Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, 20057, DC, USA

    M Li, S Ren, M T Tilli & P A Furth

  2. Program in Human Genetics, University of Maryland, Baltimore, Baltimore, 21201, MD, USA

    M T Tilli

  3. University of Maryland School of Medicine Baltimore, Baltimore, 21201, MD, USA

    J A Flaws

  4. Division of Cancer Prevention, National Cancer Institute, Rockville, 20892, MD, USA

    R Lubet

  5. University of Alabama at Birmingham, Birmingham, 35294-3360, AL, USA

    C J Grubbs

Authors
  1. M Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M T Tilli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J A Flaws
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Lubet
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C J Grubbs
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P A Furth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P A Furth.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, M., Ren, S., Tilli, M. et al. Chemoprevention of mammary carcinogenesis in a transgenic mouse model by α-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity. Oncogene 22, 2568–2572 (2003). https://doi.org/10.1038/sj.onc.1206314

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206314

Keywords

This article is cited by

Search

Advanced search

Quick links