title: Neu-induced retroviral rat mammary carcinogenesis: a novel chemoprevention model for both hormonally responsive and nonresponsive mammary carcinomas.
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.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, 1400 University Avenue, Madison, WI 53706, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Woditschka
authors.forename: Jill D
authors.initials: JD
authors.lastname: Haag
authors.forename: Jordy L
authors.initials: JL
authors.lastname: Waller
authors.forename: Dinelli M
authors.initials: DM
authors.lastname: Monson
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hitt
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Brose
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.forename: Yun
authors.initials: Y
authors.lastname: Zheng
authors.forename: Philip A
authors.initials: PA
authors.lastname: Watson
authors.forename: Kwanghee
authors.initials: K
authors.lastname: Kim
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Lindstrom
authors.forename: Bob
authors.initials: B
authors.lastname: Mau
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.forename: Michael N
authors.initials: MN
authors.lastname: Gould
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000077610:Bexarotene; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D018734:Genes, erbB-2; D005822:Genetic Vectors / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D009539:Nicotinic Acids / Q000494:pharmacology; D051381:Rats; D011920:Rats, Inbred WF; D012190:Retroviridae / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: D016588:Anticarcinogenic Agents; D009539:Nicotinic Acids; D013764:Tetrahydronaphthalenes; D013629:Tamoxifen; D000077610:Bexarotene; C095104:LG 100268