Reference SummaryGreen JE, Cancer Res 2001 Oct 15;61(20):7449-55

Title

 2-Difluoromethylornithine and Dehydroepiandrosterone Inhibit Mammary Tumor Progression but not Mammary or Prostate Tumor Initiation in C3(1)/SV40 T/t-antigen Transgenic Mice.

Authors

 Green JE; Shibata MA; Shibata E; Moon RC; Anver MR; Kelloff G; Lubet R

Journal

 Cancer Res

Volume

 61

Issue

 20

Year

 2001

Pages

 7449-55

Abstract

 Female transgenic mice that express SV40 T/t antigens under the regulatory control of the rat C3(1) gene spontaneously develop multifocal mammary lesions that predictably evolve into invasive, hormone-independent carcinomas, whereas male mice are prone to develop prostate cancer. Chemopreventive agents were administered to female C3(1)/SV40 large T-antigen mice from 7 to 19 weeks of age, during which time the mammary lesions developed and progressed to invasive carcinomas. No significant differences in the numbers of preinvasive mammary intraepithelial neoplasia lesions (histologically similar to human ductal carcinoma in situ) were observed after 2 or 8 weeks of treatment between mice receiving either vehicle alone, dehydroepiandrosterone (DHEA), or 2-difluoromethylornithine (DFMO). However, a dose-response reduction in invasive carcinoma growth was observed for both DFMO, an inhibitor of ornithine decarboxylase, and DHEA, the primary steroid precursor to both androgens and estrogens in primates. Despite unaltered expression of the transgene, tumor incidence was reduced approximately 20% by DFMO (8000 mg/kg) and 30% by DHEA (4000 mg/kg; P < 0.05). Tumor multiplicity was reduced by approximately 50% by both DFMO and DHEA (P < 0.05). DFMO had a dose-dependent effect on total tumor burden, which was reduced by 25% at low doses (4000 mg/kg) and 70% at high doses (8000 mg/kg). DHEA reduced tumor burden by 50% and 66% at low (2000 mg/kg) and high (4000 mg/kg) doses, respectively. Interestingly, despite its inhibitory effects on tumor development, DHEA caused a dose-dependent increase of serum estradiol levels that we have previously shown to increase mammary tumor formation in this model. No effect on the development of the prostate cancer precursor lesions (prostate intraepithelial neoplasia) was observed when mice were treated with DHEA, DFMO, tocopherol acetate, selenomethionine, or 9-cis-retinoic acid, although the effects on late-stage prostate cancer development were not determined. These results demonstrate that despite the expression of the highly transforming C3(1)/SV40 large T-antigen transgene, this transgenic model can be used to study the effects of chemopreventive agents on mammary cancer progression. The tumor-inhibitory effects of DHEA and DFMO on mammary cancer growth appear to occur after the development of preinvasive lesions, suggesting that these agents inhibit tumor progression but not initiation.

Links

 J:72279 – MGI References
11606379 – National Library of Medicine/PubMed

Strain Notes

Strain Note
FVB/N-Tg(C3-1-TAg)cJeg DHEA, DFMO, and 4-HPR doses determined from preliminary toxicity studies in FVB/N mice. Dosed used were 0.4 and 0.8 of maximum tolerated dose. None of doses showed effects on body weight or mortality rates.
Doses of DHEA, DFMO, and 4-HPR used were 0.4 - 0.8 of maximum tolerated dose in FVB/N mice.

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
FVB/N-Tg(C3-1-TAg)cJeg Mammary gland adenocarcinoma
  • 2-difluoromethylornithine (DFMO)
 Mammary gland

82 - 92
FVB/N-Tg(C3-1-TAg)cJeg Mammary gland adenocarcinoma
  • dehydroepiandrosterone (DHEA)
 Mammary gland

68 - 71
FVB/N-Tg(C3-1-TAg)cJeg Mammary gland adenocarcinoma
  • N-(4-hydroxyphenyl)retinamide (4HPR)
 Mammary gland

very high
FVB/N-Tg(C3-1-TAg)cJeg Mammary gland adenocarcinoma Mammary gland

very low - 100
FVB/N-Tg(C3-1-TAg)cJeg Mammary gland mammary intraepithelial neoplasia (MIN)
  • dehydroepiandrosterone (DHEA)
 Mammary gland

observed
FVB/N-Tg(C3-1-TAg)cJeg Mammary gland mammary intraepithelial neoplasia (MIN)
  • 2-difluoromethylornithine (DFMO)
 Mammary gland

observed
FVB/N-Tg(C3-1-TAg)cJeg Mammary gland mammary intraepithelial neoplasia (MIN) Mammary gland

observed
FVB/N-Tg(C3-1-TAg)cJeg Prostate gland prostatic intraepithelial neoplasia (PIN) Prostate gland

very high
FVB/N-Tg(C3-1-TAg)cJeg Prostate gland prostatic intraepithelial neoplasia (PIN)
  • 2-difluoromethylornithine (DFMO)
 Prostate gland

very high
FVB/N-Tg(C3-1-TAg)cJeg Prostate gland prostatic intraepithelial neoplasia (PIN)
  • tocopherol acetate
 Prostate gland

very high
FVB/N-Tg(C3-1-TAg)cJeg Prostate gland prostatic intraepithelial neoplasia (PIN)
  • selenomethionine
 Prostate gland

very high
FVB/N-Tg(C3-1-TAg)cJeg Prostate gland prostatic intraepithelial neoplasia (PIN)
  • 9-cis-retinoic acid
 Prostate gland

very high