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Prostate cancer's first step

Greenberg lab discovers that loss of Rb gene in prostate cells may spark progression to cancer
Dr. Norman Greenberg
Dr. Norman Greenberg, left, and Dr. Brent Sutherland are working to find mutations that collaborate with Rb loss to drive benign conditions to cancer. Photo by Todd McNaught

A new study from the Clinical Research Division reveals what may be the earliest step of prostate cancer. The finding could open the door to new tests to predict if a cancer will become aggressive and new treatments to prevent the condition from ever progressing.

The study, conducted by Dr. Norman Greenberg's laboratory and published in the Sept. 1 issue of Cancer Research, found that when mice are engineered to lose a single copy of a gene called Rb in their prostate, they develop a precancerous condition analogous to the earliest stages of human prostate cancer. Importantly, in the absence of additional genetic defects, the mice do not develop full-blown prostate cancer.

These findings suggest that loss of Rb in prostate cells could be the initial spark that in some men eventually leads to prostate cancer, Greenberg said.

"Finding the loss of Rb is like seeing smoke," he said. "We now need to figure out the genetic predictors for fire."

His lab's next goal, he said, is to identify the additional mutations that must collaborate with Rb to drive the benign condition to cancer. Ideally, blood or other simple tests to detect these mutations could be developed to reveal predictive information about a man's type of cancer well before he is in danger.

"The idea is to set the bar for detection as early as possible," Greenberg said. "Ideally, we'd hope that a man diagnosed at an early age with prostate cancer could be assured that his cancer wasn't likely to progress or that he needed early intervention that could save his life."

Scientists have had a difficult time determining the causal relationship between genes and cancer, said Greenberg, who joined Fred Hutchinson in January.

"We've addressed this by using a mouse system that allows us to selectively eliminate genes in the epithelial cells of the prostate. Our experimental approach allows us to closely mimic what happens in man and gives us a glimpse into the natural history of the disease that we haven't had before."

Further research is needed to determine which secondary mutations can push these early stage growths into prostate cancer. Greenberg said that tests to distinguish between men who only have Rb mutations and those who have acquired additional genetic defects could help doctors decide if or when aggressive treatment is warranted.

"Right now, there is no way absolutely to predict at an early stage whether a man's prostate cancer is slow-growing and nonlethal, meaning that many men receive unnecessary treatment that can cause serious side effects," he said.

Tumor suppressor family

To identify genetic events that cause early stage prostate cancer, Greenberg and colleagues focused on the Rb gene. The gene is known to be defective in a variety of cancer types, including up to 60 percent of human prostate cancers. Rb is a member of a family of genes known as tumor suppressors, which normally work to keep cells dividing at a healthy pace. Cells with defective or missing tumor suppressors lose their brakes on cell division, a hallmark of cancer.

The researchers developed a system using mice that were genetically engineered to self-destruct one or both copies of its Rb gene in prostate cells. The important difference between these mice and the standard gene knockout strategy is that the Rb gene stays intact in all other tissues of the animal, a situation that closely resembles how genes are inactivated or lost in cancers that occur sporadically in humans.

The scientists found that upon losing even one copy of the Rb gene in prostate cells, mice developed a condition known as focal hyperplasia, characterized by precancerous growths. Nearly a year after they formed, the growths did not become cancerous.

"This suggests to us that loss of a single copy of Rb can initiate this excess cell growth but is not sufficient for cancer to develop," Greenberg said. "Perhaps the most significant finding was that loss of the second copy of Rb — an event previously thought to be essential for tumor progression — did not appear to accelerate the disease. Losing one copy was enough to get things going."

230,000 new cases each year

Prostate cancer is the second leading cause of death for men in the United States. This year, more than 230,000 men will be diagnosed with the disease, in large part due to widespread screening with the prostate-specific antigen (PSA) test. The test has been controversial because it cannot distinguish between men who have nonprogressing forms of the disease that may never cause harm and those who have aggressive cancers that require treatment. Researchers are eager to develop tests that can stratify early stage prostate cancers by their likelihood to worsen, an achievement that could spare many men from unnecessary surgery or radiation therapy.

The study was led by Dr. Lisette Maddison, a former graduate student in the Greenberg lab who is now a postdoctoral fellow at Oregon Health and Science University. Other co-authors were Dr. Brent Sutherland, a postdoctoral fellow in Greenberg's lab, and Roberto Barrios, a pathologist at Baylor College of Medicine. The work was funded by the National Cancer Institute.

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