Cancer Prevention Research Prevention of Tumorigenesis in p53-Null Mammary Epithelium by Rexinoid Bexarotene, Tyrosine Kinase Inhibitor Gefitinib, and Celecoxib

The chemopreventive effects of three agents, rexinoid bexarotene, tyrosine kinase inhibitor gefitinib, and celecoxib, were tested on mammary tumor development arising in p53-null mammary epithelium. The rexinoid bexarotene was the most efficacious inhibitor as it reduced mammary tumor development by 75% in virgin mice and significantly delayed mean tumor development by 98 days in hormone-stimulated mice. The tyrosine kinase inhibitor gefitinib reduced mammary tumor incidence by 50% in virgin mice but did not significantly delay mean tumor latency in hormone-stimulated mice. Celecoxib did not reduce tumor incidence or mean tumor latency in either of the two models. The high doses of the rexinoid and the tyrosine kinase inhibitor did not affect the progression of tumors arising from the premalignant mammary outgrowth line, PN8a. A comparison of these agents with tamoxifen shows the superiority of tamoxifen in preventing tumor development in p53-null mammary cells. Similarly, a comparison of the results of the p53 model with other transgenic models in their response to the chemopreventive agents showed that mammary tumors arising from different oncogenic events will respond differently to the different agents. The prevention of mammary tumorigenesis is a viable strategy that has been tested in conventional rodent models and recently in genetically engineered models (1). The important issues are efficacy, amount and duration of side effects, and cost. The initial strategy of continued exposure to determine efficacy and side effects has been followed by the strategy of intermittent and/or limited exposure. These latter approaches have been successfully shown in breast cancer models using retinoids and selective estrogen receptor modulators in combination (2) and with the sole exposure to the selective estrogen receptor modulator tamoxifen (3). With genetically engineered models gradually replacing conventional models in most experimental studies, prevention studies on the different genetically engineered models are becoming more common. There are more than 100 genetically engineered models of mammary cancer (4). Only a few of these models have been characterized at the cellular and molecular levels with respect to growth control, premalignant development, hormone dependence, metastatic potential, and genetic stability. The most extensively characterized models are the c-neu, c-myc, wnt, Brca-1, polyoma mT, SV40Tag, and p53-null models. Prevention studies of mammary tumorigenesis have been limited to just a few of these models. Prevention agents such as tamoxifen, 9-cis-retinoic acid, the rexinoid bexarotene (LGD1069), tyrosine kinase inhibitors (i.e., ZD1839, Iressa/gefitinib), celecoxib, and soy isoflavones have been studied primarily in the c-neu and SV40Tag models (5–13). The response of these two models to these agents varies with the genetic model and the individual agent. For instance, the rexinoid bexarotene is more effective against c-neu–induced mammary tumors than against SV40Tag mammary tumors (11, 12). In MMTV-c-neu, the agents gefitinib and bexarotene are more effective than celecoxib (5, 7, 12). Both of the above models give rise to estrogen receptor-α–negative mammary tumors. The p53-null mammary epithelial model has been extensively characterized at the pathological, cellular, and molecular levels (14–16). Estrogen receptor–positive ductal carcinoma in situ is a predominant premalignant lesion, which gives rise to tumors that are predominantly, but not exclusively, estrogen receptor negative, aneuploid, and metastatic to the lung. In the only prevention study reported in this system, the selective estrogen receptor modulator tamoxifen strongly inhibited mammary tumorigenesis (17), quantitatively equal or better than the inhibition observed in the c-neu and the SV40 large T antigen models (8, 13). In the results reported herein, we continued our studies on chemoprevention agents in mammary tumorigenesis and tested the efficacy of the retinoid bexarotene, gefitinib, and celecoxib in the p53-null mammary epithelial cell model. These three agents were chosen because they have been tested in other mouse models of mammary Authors' Affiliations: Department of Molecular and Cellular Biology and Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas and Ligand Pharmaceuticals, San Diego, California Received 06/05/2008; revised 08/06/2008; accepted 08/13/2008; published OnlineFirst 01/27/2009. Requests for reprints: Daniel Medina, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: 713-798-4483; Fax: 713-790-0545; E-mail: [email protected]. ©2009 American Association for Cancer Research. doi:10.1158/1940-6207.CAPR-08-0107 168 Cancer Prev Res 2009;2(2) February 2009 www.aacrjournals.org for Cancer Research. on June 19, 2017. © 2009 American Association cancerpreventionresearch.aacrjournals.org Downloaded from Published OnlineFirst January 27, 2009; DOI: 10.1158/1940-6207.CAPR-08-0107