Neu-induced retroviral rat mammary carcinogenesis: a novel chemoprevention model for both hormonally responsive and nonresponsive mammary carcinomas

Cancer Res. 2006 Jul 1;66(13):6884-91. doi: 10.1158/0008-5472.CAN-05-1823.

Abstract

Clinically relevant animal models of mammary carcinogenesis are crucial for the development and evaluation of new breast cancer chemopreventive agents. The neu-induced retroviral rat mammary carcinogenesis model is based on the direct in situ transfer of the activated neu oncogene into the mammary epithelium using a replication-defective retroviral vector. The resulting mammary carcinomas in intact Wistar-Furth rats exhibit a mixed hormonal response in the same proportion as has been observed in women. In intact rats, approximately 50% of mammary carcinomas can be prevented by tamoxifen treatment. In ovariectomized animals, the mammary carcinomas are hormonally nonresponsive and cannot be prevented by tamoxifen. We evaluated the efficacy of retinoic X receptor-selective retinoids (rexinoids) in this novel model of mammary carcinogenesis. The rexinoids LG100268 and bexarotene (LG1069, Targretin) were highly efficacious in the prevention of neu-induced mammary carcinomas. Dietary LG100268 at 100 mg/kg diet decreased tumor multiplicity by 32% (P = 0.0114) in intact rats and 50% (P < 0.0001) in ovariectomized rats. Bexarotene treatment at a dose of 250 mg/kg diet was associated with reductions in tumor multiplicity of 84% (P < 0.0001) and 86% (P < 0.0001) in intact and ovariectomized animals, respectively. In addition to tumor multiplicity, proliferation and apoptosis were modulated by bexarotene treatment independently of estrogen signaling. The neu-induced retroviral rat mammary carcinogenesis model represents a valuable addition to existing rodent chemoprevention models. The model is useful for assessing the efficacy of chemopreventive agents, specifically those compounds that target hormonally nonresponsive tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anticarcinogenic Agents / pharmacology*
  • Bexarotene
  • Body Weight / drug effects
  • Disease Models, Animal*
  • Female
  • Genes, erbB-2*
  • Genetic Vectors / genetics
  • Mammary Neoplasms, Experimental / genetics*
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / prevention & control*
  • Mammary Neoplasms, Experimental / virology
  • Neoplasms, Hormone-Dependent / genetics*
  • Neoplasms, Hormone-Dependent / pathology
  • Neoplasms, Hormone-Dependent / prevention & control*
  • Neoplasms, Hormone-Dependent / virology
  • Nicotinic Acids / pharmacology
  • Rats
  • Rats, Inbred WF
  • Retroviridae / genetics
  • Tamoxifen / pharmacology
  • Tetrahydronaphthalenes / pharmacology

Substances

  • Anticarcinogenic Agents
  • Nicotinic Acids
  • Tetrahydronaphthalenes
  • Tamoxifen
  • Bexarotene
  • LG 100268