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

Minglin Li, Shuxun Ren, Maddalena T. Tilli, Jodi A. Flaws, Ronald Lubet, Clinton J. Grubbs, Priscilla A. Furth

Research output: Contribution to journalArticle

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 10g/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 (10g/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.

Original languageEnglish (US)
Pages (from-to)2568-2572
Number of pages5
JournalOncogene
Volume22
Issue number17
DOIs
StatePublished - May 1 2003
Externally publishedYes

Fingerprint

Eflornithine
Cyclin D1
Chemoprevention
Transgenic Mice
Carcinogenesis
Breast
Diet
Breast Neoplasms
Neoplasms
Viral Tumor Antigens
Cell Survival
Biomarkers
Cell Proliferation
Apoptosis
Growth

Keywords

  • Apoptosis
  • Cell proliferation
  • Cyclin D1
  • DFMO
  • Mammary cancer progression
  • Transgenic mouse model

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Chemoprevention of mammary carcinogenesis in a transgenic mouse model by α-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity. / Li, Minglin; Ren, Shuxun; Tilli, Maddalena T.; Flaws, Jodi A.; Lubet, Ronald; Grubbs, Clinton J.; Furth, Priscilla A.

In: Oncogene, Vol. 22, No. 17, 01.05.2003, p. 2568-2572.

Research output: Contribution to journalArticle

Li, Minglin ; Ren, Shuxun ; Tilli, Maddalena T. ; Flaws, Jodi A. ; Lubet, Ronald ; Grubbs, Clinton J. ; Furth, Priscilla A. / Chemoprevention of mammary carcinogenesis in a transgenic mouse model by α-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity. In: Oncogene. 2003 ; Vol. 22, No. 17. pp. 2568-2572.
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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 10g/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 (10g/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.",
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