ABSTRACT
Breast cancer is the most prevalent tumor in American woman. Multiple factors, including age, diet, genetics, environment, geographic location, parity, as well as race, influence the development of this heterogeneous disease. As the process of oncogenesis involves the disruption of diverse cellular pathways including cell cycle, growth, survival, and apoptosis, the high throughput technique of microarray analyses provides a powerful insight into multiple cellular processes. These techniques have identified particular expression patterns that can classify tumors into new groups and aid in the prediction of the natural history of the disease and the therapeutic response. This wealth of information may also form the basis for the development of new types of targeted therapies. Studies to identify the earliest molecular events in oncogenesis and progressive changes in the human disease have been difficult to perform within the same patient. The use of transgenic mouse mammary cancer models provides an opportunity to decipher molecular changes that occur at progressive stages of tumor development. This paper reviews microarray technology, and the insights gained from published breast cancer microarray analyses, and considers the contribution of microarray studies in identifying mouse cancer models that may be appropriate for answering particular experimental questions.
Subject(s)
Breast Neoplasms/genetics , Gene Expression Profiling , Mammary Neoplasms, Experimental/genetics , Oligonucleotide Array Sequence Analysis/methods , Animals , Breast Neoplasms/pathology , Disease Progression , Female , Humans , Mammary Neoplasms, Experimental/pathology , Mice , Neoplasm Proteins/geneticsABSTRACT
Breast cancer is a leading cause of cancer morbidity and mortality. Given that the majority of human breast cancers appear to be due to non-genetic factors, identifying agents and mechanisms of prevention is key to lowering the incidence of cancer. Genetically engineered mouse models of mammary cancer have been important in elucidating molecular pathways and signaling events associated with the initiation, promotion, and the progression of cancer. Since several transgenic mammary models of human breast cancer progress through well-defined cancer stages, they are useful pre-clinical systems to test the efficacy of chemopreventive and chemotherapeutic agents. This review outlines several oncogenic pathways through which mammary cancer can be induced in transgenic models and describes several types of preventive and therapeutic agents that have been tested in transgenic models of mammary cancer. The effectiveness of farnesyl inhibitors, aromatase inhibitors, differentiating agents, polyamine inhibitors, anti-angiogenic inhibitors, and immunotherapeutic compounds including vaccines have been evaluated in reducing mammary cancer and tumor progression in transgenic models.
Subject(s)
Antineoplastic Agents/pharmacology , Mammary Neoplasms, Experimental/drug therapy , Angiogenesis Inhibitors , Animals , Antineoplastic Agents/therapeutic use , Cell Cycle/drug effects , Cell Differentiation/drug effects , Drug Evaluation, Preclinical/methods , Female , Immunotherapy , Mammary Neoplasms, Experimental/etiology , Mice , Mice, Transgenic , Signal Transduction/drug effectsABSTRACT
Conjugated linoleic acid (CLA) is a chemoprotective fatty acid that inhibits phorbol ester-induced skin tumor promotion in mice. The goal of the present study was to determine potential chemoprotective mechanisms through which CLA may be acting. Mice were fed diets containing 0.0%, 0.5%, 1.0%, or 1.5% CLA (by wt) for six weeks. The epidermis was evaluated for fatty acid composition, vascular permeability, prostaglandin E2 (PGE2) production, hyperplasia, ornithine decarboxylase activity, and c-myc mRNA accumulation. Fatty acid analysis of mouse epidermis demonstrated a dose-dependent increase of CLA incorporation into phospholipids and neutral lipids. In mice topically treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), dietary CLA (1.5%) significantly (p < 0.05) reduced PGE2 synthesis (2-fold). Additionally, CLA lowered accumulation of c-myc mRNA, a gene commonly associated with regulating cell cycle components involved in cellular proliferation, although this trend was not significant. Vascular permeability was unaffected by dietary CLA. These data suggest that dietary CLA modulates TPA-induced tumor promotion through a mechanism involving PGE2 production; however, dietary CLA had a moderate effect on c-myc mRNA levels and little effect on TPA-induced hyperplasia and ornithine decarboxylase activity.
