Preclinical in vitro models from genetically engineered mice for breast and colon cancer (review)

Abstract

Genetically engineered mice with targeted alterations in clinically relevant oncogenes, tumor suppressor genes or DNA mismatch repair genes provide unique predictive animal models for human carcinogenesis, and cancer prevention/ therapy. However, some of the genetically engineered mouse models lack target organ specificity for colon carcinogenesis. We have established, characterized and validated stable epithelial cell lines from 'normal' and 'genetically' predisposed target organs that offer innovative and mechanistic approaches, complementing in vivo studies on existing animal models for clinical breast and colon cancer. Epithelial cell lines with up-regulated Ras or myc oncogene, mutated Apc tumor suppressor gene and Mlh1 DNA mismatch repair gene provide facile experimental systems for organ site carcinogenesis and cancer prevention. Altered expression of cancer specific biomarkers and their modulation by several synthetic pharmacological agents such as retinoids, selective estrogen receptor modulators, non-steroidal anti-inflammatory drugs and specific enzyme inhibitors have been reported from our laboratory. Oncogene expressing MMEC-Ras and MMEC-myc mammary epithelial cells, Apc mutant 850 Min COL and 1638N COL, and DNA mismatch repair/Ape mutant Mlh 1/1638N COL colon epithelial cells exhibit aberrant cell cycle progression, down-regulated apoptosis and enhanced carcinogenic risk in vitro and tumor formation in vivo. We have reported that relative to the parental 'normal' non-neoplastic cells, genetically 'altered' pre-neoplastic cells exhibit enhanced sensitivity for growth arrest by multiple mechanistically distinct pharmacological agents. Comparative experiments on isogenic 'normal' and genetically 'altered' target cell lines facilitate cancer selective efficacy and identification of susceptible mechanistic pathways. Treatment of these genetically 'altered' pre-neoplastic cells with low dose combination of mechanistically distinct pharmacological agents as well as naturally occurring phytochemicals induce cytostatic growth arrest, alter cell cycle progression and reduce carcinogenic risk The availability of validated technology for model development, and for mechanism based biomarker assays now establishes a novel platform to rapidly test carcinogenicity and preventive/therapeutic efficacy of novel pharmacological agents as well as naturally occurring phytochemicals. Thus, these data permit rational prioritization of efficacious lead compounds for preclinical testing and future clinical trials for prevention/ therapy of breast and colon cancer.