New understanding of cancer initiation

Researchers at the University of Nebraska Medical Center (UNMC) in Omaha have assisted in a significant discovery - the understanding of a common mechanism of cancer initiation - that could result in better cancer assessment, prevention and detection.

“We have a novel approach to cancer. We know the initiating step,” said Ercole Cavalieri, Ph.D., of the University of Nebraska Medical Center. “We think prevention of cancer can be solved by eliminating this initiating step.”

Eleanor Rogan, Ph.D., a UNMC research collaborator, continued: “We have found the first step that starts a cell down the road to becoming a cancer cell. By preventing this first step from happening, we think we can stop the development of breast or prostate cancer. The combination of an early detection test for cancer risk with administration of preventing agents should enable us to significantly reduce the number of women and men that develop breast or prostate cancer.”

The researchers have discovered that certain estrogen derivatives (metabolites) can react with deoxyribonucleic acid (DNA) to cause damage that may initiate a series of events leading to breast, prostate and other cancers. They found evidence in a simple urine test in humans. Estrogens can initiate cancer when natural mechanisms of protection do not work properly in the body, allowing estrogen metabolites to react with DNA.

“If these protections are insufficient, due to genetic, lifestyle or environmental influences, we think cancer can result,” Dr. Cavalieri said. “Now that we have the basic knowledge about this unifying mechanism of cancer initiation, we have a greater sense of urgency to assess people at risk and, at the same time, begin studies of prevention by using specific natural compounds.”

The findings are published in the December issue of the International Journal of Cancer. Findings were confirmed in a second, larger study and presented at a recent gathering of international scientists and physicians in San Antonio, Texas. The study involves researchers at the University of Nebraska Medical Center, Mayo Clinic and the Italian National Cancer Institute. A majority of the study was funded by the U.S. Army Breast Cancer Research Program Center of Excellence Award. Similar findings were reported and published about prostate cancer in the journal The Prostate in 2006.

The screening test developed by the researchers analyzes estrogen metabolite profiles in humans and can simultaneously associate the profile with risk of getting breast cancer. It involves testing a one-ounce sample of urine using a sophisticated method called tandem mass spectrometry, which analyzes about 40 estrogen-related compounds, including estrogen-DNA adducts formed by a chemical reaction of estrogen metabolites and DNA.

Researchers say the results are exciting because they show women at high risk of breast cancer can be identified by the level of adducts in a urine sample.

Researchers analyzed estrogen-DNA from 46 women with normal risk for breast cancer, 12 women at high risk of developing breast cancer, and 17 women diagnosed with breast cancer. They found women at high risk of breast cancer and the women with breast cancer had significantly higher levels of the estrogen-DNA adducts in their urine samples, while the women with normal risk for breast cancer had low levels.

“This is a very big step because we have a test in humans to determine the risk of getting breast or prostate cancer long before the tumor appears,” Dr. Cavalieri said. “We can use these estrogen-DNA adducts as a measure of cancer risk. In addition, we have begun to establish how effective natural compounds may be at preventing cancer by determining their ability to reduce the levels of these adducts in urine.”

He also said accumulating evidence suggests that specific metabolites of estrogens, if abundantly formed, can become cancer-initiating agents by reacting with DNA and generate mutations leading to cancer. DNA is composed of four bases, called adenine, guanine, cytosine and thymine, the alphabet of genetic information.

Estrogen metabolites react predominantly with the first two DNA bases, adenine and guanine, to form estrogen-DNA adducts, Cavalieri said. The resulting damage generated by the reaction can give rise to mutations that eventually initiate cancer. The important estrogen-DNA adducts spontaneously fall out of the DNA, leaving behind gaps that generate the cancer-initiating mutations.

The estrogen-DNA adducts eventually make their way out of cells and are excreted in urine.

“This finding identifies a new biomarker in the urine which appears to correlate with a women's risk of developing breast cancer,” according to Kenneth Cowan, M.D., Ph.D., director of the UNMC Eppley Cancer Center. “While these studies need to be confirmed in a prospective study in a larger group of patients, this could become an important screening assay for women and could lead to new therapies to prevent breast cancer.”

Dr. Cavalieri said one of the major obstacles in cancer research is related to the concept that cancer is a problem of 200 diseases, a viewpoint that has impeded researchers from looking at the origin of cancers because the search would be prohibitively complex. And for this reason, he said, the origin of breast, prostate and other human cancers has been virtually unknown.

While the expression of various cancers coincides with the concept of 200 diseases, some scientists believe a common origin is a factor for many prevalent types of cancer. There is widespread agreement in the scientific community that cancer is triggered by genetic mutations in critical genes, he said.

Jose Russo, M.D., senior member from the Fox Chase Cancer Center in Philadelphia, said: “The article is the best example of translational research. They have generated a unified concept of carcinogenesis and obtained a practical marker detectable in the urine of breast cancer patients. This article provides the adequate setting to explore this concept further by laying the basis to prepare a set of prospective clinical trials testing the preventive effects of the agents or mixtures of agents that can intercept the initiation event in breast or other cancers.”

David G. Longfellow, Ph.D., president and chief executive officer of the Toxicology Forum, an international, nonprofit organization devoted to conducting open dialogues among various segments of society concerned with problems in toxicology, said the work represents a paradigm shift in detection of cancer risk in humans and provides the earliest possible rational marker for prevention strategies and regimens.

“This work conveys a very exciting message that breast and prostate cancer risk can be identified years before the development of a tumor and suggests that natural preventive agents may be effectively used to prevent the initiation step in cancer,” Dr. Longfellow said. “Although this is a single manuscript, it is based on an extensive body of work in animal models and humans which consistently supports these findings and is complemented by collaboration with many international cancer scientists.”

For more information:
Go to UNMC's Web site at http://www.unmc.edu.
The link to the study is: http://www3.interscience.wiley.com/cgi-bin/abstract/117869053/ABSTRACT.

About the University of Nebraska Medical Center
UNMC is located in Omaha, Nebraska, and is the only public health science center in the state. Its educational programs are responsible for training more health professionals practicing in Nebraska than any other institution. Through their commitment to education, research, patient care and outreach, UNMC and its hospital partner, The Nebraska Medical Center, have established themselves as one of the country's leading centers in cancer, transplantation biology, bioterrorism preparedness, neurodegenerative diseases, cardiovascular diseases, genetics, biomedical technology and ophthalmology. UNMC's research funding from external sources is now nearly $80 million annually and has resulted in the creation of more than 2,400 highly skilled jobs in the state. UNMC's physician practice group, UNMC Physicians, includes more than 460 physicians in 50 specialties and subspecialties. They practice primarily in The Nebraska Medical Center, UNMC's teaching hospital.