Cancer is a disorderly affair in which cells go out of control--proliferating rapidly, refusing to die, overwhelming the body's defenses, and eventually growing into tumors. To fight this scourge, SIUC researchers in science, medicine, and agriculture are working at the molecular level. Their research explores fundamental biological processes; it goes by the heading of basic science. But some of these projects are leading to possible applications--holding out the hope of improved diagnostic tests, new cancer therapies, and custom-designed materials for drug-delivery systems.

Understanding each complex piece of the cancer puzzle takes years. Sometimes leads that seem promising fizzle out. But negative results can be as important as positive ones, because they help scientists refine their efforts. One way or another, by indirect and sometimes surprising means, molecular-scale explorations in the lab eventually pay off in the doctor's clinic. The key to cancer is understanding what can go wrong with the intricate dance genes and proteins do, every day, to keep us alive--and how to counter what goes wrong.

The right stuff

To do their job, genes must be expressed: translated into proteins. In a process called transcription, the DNA in our genes acts as a template for the assembly of RNA molecules. These RNA molecules shuttle off to special areas of the cell, where they in turn serve as templates for the assembly of proteins from amino acids. Proteins drive the business of the cell--and thus the business of life and death.

Genes must be expressed at the right times and to the right degree. If the wrong proteins are being made at the wrong times, or in the wrong amounts, it opens the door for all kinds of trouble, including cancer. Special proteins called transcription factors govern gene activity, latching on to genes and controlling their expression. These factors regulate protein levels in the cell by boosting, decreasing, or shutting off RNA transcription.

SIUC physiology professors Jodi Huggenvik and Michael Collard, who study biological processes at the molecular level, have been teasing out the function of a transcription factor called DEAF-1, which plays a crucial role in embryo development and neuron functioning. Their research strongly suggests that it also is connected with cancer.

"Genes involved in embryonic development need to be on during a very specific time and then usually need to be shut off--you don't need them as an adult," Collard says. "DEAF-1 may function in shutting off these very powerful genes that drive development. That can relate to cancer: if you have mutations in DEAF-1, then genes that should be suppressed may get activated."

DEAF-1 was first identified in 1996, in fruit flies. In 1998, Rhett Michelson, one of Huggenvik's doctoral students, stumbled across a similar transcription factor in monkey cells. The SIUC research team soon identified the same factor in human and rat cells and eventually determined that it was the mammalian version of DEAF-1. (Researchers have since identified DEAF-1 in other species as well; it probably occurs in all animals.)

"We got very excited about this transcription factor," Collard says, "because when we looked at its amino-acid structure, we saw similarities with a number of other transcription factors that are involved in cancer." When the researchers studied the chemical sequence of the DNA that codes for the DEAF-1 protein, their suspicions were reinforced.

They also found evidence of a cancer connection in GenBank, a worldwide database that archives DNA sequences from around the world. "People have submitted DNA sequences from cancer patients, that correspond to DEAF-1, but we find that these sequences are often mutated," Huggenvik says.

Putting the brakes on cancer

DEAF-1 may be a tumor suppressor--a gene that puts the brakes on cancer. In cell experiments, Huggenvik and Collard have found that the DEAF-1 protein normally suppresses a particular gene which is overexpressed in lung cancer. The research team now is deleting the DEAF-1 gene from specific tissues in mice to see if cancer results.

If DEAF-1 is indeed a tumor suppressor, mutations may destroy its anti-cancer power. In fact, says Collard, "If we mutate DEAF-1 [in test-tube experiments], it seems to act like an oncogene--a gene that drives cancer."

Huggenvik and Collard's early research on DEAF-1 was funded by the American Cancer Society and by internal SIUC grants. In 2001 the National Cancer Institute awarded the two scientists a five-year, $1.17 million grant to investigate whether DEAF-1 is a tumor suppressor for Wilms' tumors, a type of kidney cancer in children.

One clue in that regard relates to gene inheritance and expression. We inherit two copies of each chromosome and hence two copies of each gene--one from our mother and one from our father. Usually both copies of a gene are expressed in the cell. Having this diversity is like having an insurance policy: if one copy of the gene becomes damaged, the cell has a backup.

In the case of a few genes, however, only the maternal or only the paternal copy is expressed. In gene-speak, the other copy is "silenced." These are called imprinted genes.

Imprinting must serve some important physiological purpose, because it comes at a high price: no backup. The silenced copy of the gene can't take over if something goes wrong. And cancer is a classic case of that.

As tumor cells divide and multiply, they often kick out "normal" copies of genes and duplicate mutated or silenced copies. It's significant, then, that cells from Wilms' tumors almost always contain two paternal copies of the chromosome region where DEAF-1 is found--and no maternal copies. This chromosome region may host an imprinted tumor suppressor gene that ends up totally silenced in Wilms' tumors because the active copy is missing.

Huggenvik and Collard think that DEAF-1 is the most likely candidate for that tumor suppressor gene. Certain complexities in the way it's transcribed suggest it is an imprinted gene, and the chromosome region where it's located--the tip of the small arm of chromosome 11--contains other imprinted genes. This region of chromosome 11 seems to be mutated or silenced in many human diseases, including ovarian, lung, colon, breast, and prostate cancer.

DEAF-1 and prostate cancer

While Huggenvik and Collard continue to test that hypothesis, a new National Cancer Institute grant is allowing them to explore DEAF-1's role in prostate cancer. Co-investigators Kounosuke Watabe and Thomas Tarter, faculty at the SIU School of Medicine in Springfield, are establishing a tissue bank for this study and helping to analyze protein expression in cells.

In pilot work, the team found that DEAF-1 levels were low or nonexistent in half of the prostate tumor samples they analyzed. The lower the levels, the less likely the patient was to survive.

If these early findings hold up in wider-scale testing, doctors might soon be able to use DEAF-1 levels to more accurately diagnose prostate cancer and gauge a patient's prognosis--information that could influence treatment.

Huggenvik and Collard also will try to determine what causes decreased levels of the DEAF-1 protein in prostate cancer. It could be due to gene mutations. But there is another possibility that holds more promise for patients.

Genes are sometimes switched on or off when they shouldn't be because chemical units called methyl groups have bound to them. "The main way gene imprinting seems to be regulated is through DNA methylation," says Collard. In some types of cancer, in fact, it's already known that a tumor suppressor gene is being silenced because of DNA methylation.

"Right now, in clinical trials, [biomedical researchers are] trying chemicals that might interfere with methylation," Collard adds. "They're hopeful that when genes get silenced [in the disease process], they can turn them back on, and vice versa." If the DEAF-1 gene is being silenced through methylation in prostate cancer, perhaps some type of drug treatment could reverse it.

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