National Institute of Environmental Health Sciences
Prostate cancer is a disease of enormous public health importance; it is the most frequently diagnosed cancer in American men. However, little is understood about its pathogenesis. Effective prevention will depend on research into how genetic predisposition and environmental exposures the risk of prostate cancer. The National Institute of Environmental Health Sciences (NIEHS) is spearheading this approach to understanding gene-environment interactions in prostate cancer development, with the help of several key initiatives.
Environmental Genome Project: Human diseases, such as prostate cancer, are generally the consequence of both genetic susceptibility and environmental exposure. The tools of molecular genetics provide new opportunities to understand the genetic basis for individual differences in susceptibility to environmental exposure. The NIEHS is expanding its research program on genetic susceptibility to environmentally-associated diseases through a new Environmental Genome Project. Over the next five years, the Environmental Genome Project would systematically identify the allelic variants of disease susceptibility genes in the U.S. population, develop a central database of known polymorphisms for these genes, and foster population-based studies of gene-environment interaction in disease etiology. By identifying those genes and allelic variants that affect individual response to environmental toxins, we can better predict health risks and develop environmental policies to protect the most vulnerable subgroups of the population from such diseases such as prostate cancer.
The NIEHS Environmental Genome Project would be a broad, multi-center effort to identify systematically in the U.S. population the alleles of environmental disease susceptibility genes. Susceptibility genes will be chosen through a peer-reviewed process and are expected to include five broad gene classes: genes controlling the distribution and metabolism of toxicants; genes for the DNA repair pathways; genes for the cell cycle control system; cell death/differentiation genes; and, genes for signal transduction systems controlling expression of the genes in the other classes. This effort would result in the systematic identification of the polymorphisms of these genes found in the U.S. population. A central database of the polymorphisms would be made available. This database will support both functional studies of alleles and population-based studies of disease risk.
Exposure Assessment Initiative: The NIEHS and the Centers for Disease Control and Prevention are collaborating on improving the exposure assessment of a particular group of environmental exposures--the environmental endocrine disruptors which could contribute substantially to the understanding of how environmental chemicals may promote or induce prostate cancer. This collaboration will strengthen the science base for risk assessments by quantifying the amount of a given chemical or a chemical structural class in the human body as a consequence of exposure from daily living. In the case of environmental endocrine disruptors, we know that there are scores of environmental chemicals that possess hormonal activity, including pesticides, industrial byproducts, health care products and compounds arising from the manufacture and use of plastics and detergents. In addition, there are numerous plant and fungal products that also possess hormonal activity and are known to produce health effects when people are exposed to them insufficient quantities. Unfortunately, we know very little about the human body burden of these chemicals and this lack of knowledge creates much of the controversy over their impact on human health. This information is needed before we can make a more science-based evaluation of whether these environmental agents are producing effects on hormonally sensitive diseases such as prostate cancer.
cDNA Microarray Analysis of Gene Expression: cDNA microarrays are tools that can be used to analyze changes in genome-wide patterns of gene expression. This technology may revolutionize the way toxicological problems are investigated. Given that exposures to different classes of toxicant result in distinct patterns of altered gene expression, microarray technology can be used to categorize and classify these effects through the direct comparison of gene expression patterns in control versus treated samples on the same cDNA microarray. In defined model systems, treatment with known agents, dioxin-like compounds, or estrogenic chemicals may provide a gene expression "signature" on a microarray which represents the cellular response to these agents. These same systems can then be treated with unknown, suspect agents to determine if one or more of these standard signatures is elicited. This approach will also help elucidate an agent's mechanism of action and may also be used to detect changes in exposed human populations. It is also likely that new molecular targets of toxicant action will be identified, and that these new targets may be good candidates for analysis in the Environmental Genome Project.
The NIEHS is in the process of establishing cDNA microarray technology in a collaborative research effort with the National Human Genome Research Institute. Custom cDNA arrays or "chips" are being developed that comprise human cDNA clone subarrays oriented toward detection of the expression of genes involved in responses to toxic insult. The goals of the project are to use gene expression methodologies to: 1) identify toxicants on the basis of tissue specific patterns of gene expression (molecular signature); 2) elucidate mechanisms of action of environmental agents through the identification of gene expression networks; 3) use toxicant-induced gene expression as a biomarker to assess human exposure; 4) extrapolate effects of toxicants from one species to another; 5) study the interactions of mixtures of chemicals; and 6) examine the effects of low dose exposures versus high dose exposures. In addition, gene expression profiles are likely to be excellent surrogate markers of safety and efficacy for use in clinical trials, which face a similar "bottleneck" effect to that identified for toxicology studies. Future resources in the area of prostate cancer could be applied, in part, to the NIEHS effort to develop cDNA microarray technology for the elucidation of prostate-specific patterns of gene expression resulting of exposure to low level environmental toxicants either singly or in mixtures. Funds would also be targeted to identify gene expression networks that may lead to the induction and/or progression of prostate cancer.
New Models for Prostate Cancer Research: There is a lack of appropriate animal models for prostate cancer. NIEHS researchers are working with a new mouse model called TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate). These mice develop prostate cancer by six months of age. A colony has been established, and the first study will be to characterize the pathogenesis of lesion development and related parameters in target tissues. Researchers are also interested in the modulation of IGF-I and in determining how this affects the pathogenesis and development of the prostate cancer in the TRAMP model.
Environmental Family Cohort: Some of the most significant public health findings have arisen from large, long-term cohort studies. The two prime advantages of any cohort study are that careful exposure information can be collected before disease occurs, and many different disease outcomes can be addressed in a single setting. Previous cohorts established to study such factors as diet and risk of cancer and other diseases collected little information on environmental exposures and have not been selected to maximize the possibility of exposure. The NIEHS is studying the feasibility of establishing a cohort of people who live in areas with a high burden of exposure to environmental pollutants (e.g., parts of Louisiana, New Jersey, or Los Angeles). Special efforts would be made to enroll persons from different ethnic minorities. Over time, the health problems, including prostate cancer, that develop in this cohort would provide rich opportunities for specific studies. Studies of prostate cancer and other specific diseases in this cohort would permit testing of candidate susceptibility genes as part of the Environmental Genome Project.
Vitamin D Receptor Polymorphisms and Prostate Cancer Risk: NIEHS researchers have demonstrated an association between a polymorphism in exon 9 of the vitamin D receptor (VDR) and increased prostate cancer risk. Prostate cancer cases and controls are currently being analyzed for VDR polymorphisms. The goal is to characterize the association of genetic polymorphisms in the VDR and the development of prostate cancer that has previously been described. Opportunities exist to accelerate this project as well as enable the NIEHS to extend it to additional polymorphisms using results from the Environmental Genome Project.
Genetic Susceptibility and the Environment in Prostate Cancer Risk: The research on genetic susceptibility tests the hypothesis that commonly inherited allelic variants of certain genes, in conjunction with environmental exposures, affect a person's risk of developing disease. The primary focus of this work has been on bladder cancer, although recently we have expanded to include studies of prostate. NIEHS researchers have obtained DNA samples with linked epidemiologic information with which to extend earlier findings of an association between a polymorphism in the 3'UTR of the vitamin D receptor gene and prostate cancer risk. Genotyping has been completed and data analysis is to begin. In addition, researchers have genotyped prostate cancer cases and controls for a polymorphism in CYP17, a gene involved in androgen metabolism, and are starting data analysis. Opportunities exist to accelerate this project as well as enable the NIEHS to extend it using results from the Environmental Genome Project.
Metastasis Suppressor Gene for Prostatic Cancer: Progression of cancer to the metastatic state involves multiple cellular and genetic changes, including the loss of metastasis suppressor functions and the activation of oncogenes. NIEHS researchers cloned a gene, termed KAI1, that can suppress the metastatic ability of a rat prostatic cancer cell line. KAI1 is highly expressed in normal prostate and breast epithelial cells but is dramatically lower in cancer cell lines derived from metastatic tumors. Primary and metastatic tumor specimens have been collected from prostate, colon, breast, and ovarian tumors to investigate whether KAI1 expression can be used to predict the metastatic ability of primary cancers. Current work involves the characterization of the regulation of KAI1 function and an examination of the role of KAI1 in cell-cell aggregation, adhesion, and invasion. This work is expected to result in a model that would allow the development of KAI1 gene therapy protocols. Opportunities exist to accelerate and extend this project. For example, a possible metastasis suppressor gene has been identified on chromosome 8p; this gene would be cloned and characterized.