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 WistarFurth rats exhibit a mixed hormonal response in the same proportion as has been observed in women. In intact rats, f50% 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. (Cancer Res 2006; 66(13): 6884-91)

The non-protein coding breast cancer susceptibility locus Mcs5a acts in a non-mammary cell-autonomous fashion through the immune system and modulates T-cell homeostasis and functions

“…To rule out the possibility that Mcs5a affects the metabolic activation of DMBA, mammary carcinomas were induced by two additional treatments, namely carcinogenesis using the directly alkylating agent NMU and mammary ductal infusion of replication-defective retrovirus expressing the activated HER2/neu oncogene ( HER2/neu ) [15]. DMBA-, NMU-, and HER2/neu -induced mammary carcinoma multiplicities were compared between the susceptible congenic control line and the Mcs5a -resistant congenic line.…”

“…Female rats (age of 50 to 55 days) were orally gavaged with 7,12-dimethylbenz(a)anthracene (DMBA) at 65 mg/kg of body weight or were injected intraperitonially with N -nitroso- N -methylurea (NMU) at 50 mg/kg of body weight or were subjected to mammary ductal infusion of replication-defective retrovirus expressing the activated HER2/neu oncogene ( HER2/neu ) at a concentration of 5 × 10 5 to 1 × 10 6 colony-forming units (CFU) per milliliter [15]. To obtain in situ carcinomas (ISCs), female rats of 50 to 55 days of age were subjected to HER2/neu infusion at 1 × 10 7 CFU/mL [16].…”

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

“…In contrast, the rexinoid LG100268 (LG268, see Fig 1A for structure) has been reported to have adverse effects on both TG and T4 levels in rodent studies (12,13). Despite these undesirable actions, LG268 is well tolerated in both rats and mice and has been an extremely potent and useful agent for both prevention and treatment of experimental breast and lung cancer (14)(15)(16)(17)(18)(19)(20).…”

Characterizing a Rat Brca2 Knockout Model

“…In addition, mammary carcinomas induced by the retroviral infusion of activated neu result in DCIS-like hyperplasias that develop into frank carcinomas. A large portion of these mammary cancers are hormone responsive, just like human breast cancer, which makes this model highly relevant for chemoprevention studies [39].…”

“…A large portion of the carcinomas (~50%-60%) responded to hormone ablation by ovariectomy [1] or can be prevented by treatment with the antiestrogenic drug tamoxifen Gould, Michael N. W81XWH-04-1-0436 [39]. Tamoxifen treatment also prevents ~50% of invasive breast cancer in women [40], again illustrating the relevance of the rat neu infusion model to human breast cancer and more specifically chemoprevention.…”