Peroxisome proliferators (PPs) are a large group of chemicals which when fed to rodents result in a characteristic hepatomegaly, proliferation of peroxisomes in parenchymal cells, and an increase in peroxisomal β-oxidation of fatty acids. These chemicals have raised a health concern since there is a high likelihood of human exposure and an association between peroxisome proliferation and liver cancer in laboratory animals has been well documented. Throughout the 1970s and 1980s, much of the research on PPs focused on their biochemical effects in laboratory animals, such as alterations in lipid metabolism and enzyme induction. Upon the discovery of a nuclear hormone receptor that is activated by PPs in 1990 by I. Issemann, S. Green and colleagues the research has taken a dramatic turn toward molecular and cellular biology. The new era in peroxisome proliferator research focuses on this intracellular protein aptly named the peroxisome proliferator-activated receptor or PPAR. PPs are now considered to cause cancer in a manner similar to other steroid hormone receptor ligands such as estrogen, i.e. by altering gene expression and affecting the phenotype of the target cell. PPARs have been cloned in several species, including humans, which help explain the molecular events involved in PP-dependent gene regulation. The cloning of three distinct PPARs from xenopus, lead to the realization that a subfamily of these receptors existed. Currently, the subfamily has been defined as PPARα, PPARβ (also called PPARδ and NUC1) and PPARγ. The potency of various chemicals to activate PPARs is subtype specific and the expression of PPARα, β and γ varies widely from tissue-to-tissue. Thus each receptor has distinct ligands and has evolved to serve different biological role.
Several hypolipidemic drugs and industrial chemicals classified as PPAR ligands result in tumors in laboratory animals. Conversely, ligands for PPARγ have been associated with an inhibition of cancer of the colon, prostate and breast. A theory that has been gaining favor over recent years is that PPAR ligands affect the carcinogenic process by altering the expression of a particular subset of genes that in turn affects the rate of proliferation of cells. That PPARs are required for the effects of their ligands on cell proliferation has become apparent through the use of knockout animals. PPARα null mice do not respond to the tumor promoting effects of peroxisome proliferators and PPARβ null mice have altered response to mitogens. Taken together, this information indicates there is a direct link between peroxisome proliferators, PPAR, altered gene expression, and toxicity and/or therapeutic effects.
Studies proposed in this progress (submitted as a Program Project Grant) will test the effect of dietary energy restriction (DER) and/or the omega-3 fatty acid DHA on mammary carcinogenesis in an obesogenic rodent model and on breast cancer risk reduction in overweight and obese women. State-of-theart lipidomic analysis will identify the DHA metabolites responsible for the chemopreventive effect of DHA. This work is expected to lead to new prevention strategies effective against ER+ and ER- breast cancer and acceptable to women at risk because of the health promoting feature of our interventions.
Molecular Toxicology 101 for the lay-person.