U.S. Army Medical Research and Materiel Command
September 27, 2002
NATURAL COMPOUNDS FROM PLANTS AND ANIMALS MAY PROVE USEFUL IN SUPPRESSING MAMMARY TUMORS
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Research Results from the "Era of Hope "Department of Defense Breast Cancer Research Program Meeting
ORLANDO, September 27, 2002 - In health as in sports, the best defense is a good offense: preventive strategies to fend off disease before it develops and requires treatment. Studies presented at the "Era of Hope" Department of Defense Breast Cancer Research Program meeting demonstrate that two very different dietary supplements, one from soy plants and the other from certain animals, may have significant preventive effects against mammary tumors in rats and mice by influencing the process by which cells differentiate for specific functions.
Novel Cancer-Inhibiting Mechanism Identified for Substance Found in Animal Fat
Conjugated linoleic acid (CLA), a minor fatty acid found in meat and dairy products, inhibits mammary cancer in animal models by altering mammary stromal cell differentiation and reducing angiogenesis - the formation of blood vessels that feed tumors, reported researchers from Roswell Park Cancer Institute in Buffalo, NY.
"In a series of in vitro experiments, we found that CLA strongly influenced stromal cells in rat mammary glands to become fat cells and impeded angiogenesis," explained Margot Ip, Ph.D., from the Institute's Department of Pharmacology and Therapeutics. In follow-up studies, angiogenesis was reduced by approximately 80% in mice fed low levels of CLA for six weeks.
Rat mammary glands contain stromal cells that are multipotent, meaning that they can develop into one of several types of cells: fat cells (adipocytes), blood vessel-lining cells (endothelial cells), or connective tissue-producing cells (fibroblasts).
Interestingly, although CLA produced more fat cells in vitro the CLA-fed mice did not show a similar increase in number of fat cells.
Testing their theory that programmed cell death (apoptosis) occurs at some point after CLA prompts differentiation to fat cells, the researchers are measuring the number, size, and apoptotic frequency of fat cells in CLA-treated mice to see whether some of these cells are induced to undergo programmed cell death. They are also using a mouse model that overexpresses a protein commonly associated with human breast cancer to test the effect of CLA in those animals.
Dr. Ip's group hopes to confirm that CLA can recruit stromal cells away from capillary formation to reduce the pool available for angiogenesis thereby suggesting a role for natural enrichment of foods in preventing or delaying breast cancer.
"Many questions must be answered, such as which CLA isomers are best, but CLA may one day be an appropriate component of a preventive approach to breast cancer for postmenopausal women who are at a high risk for developing breast cancer," added Dr. Ip. Studies are under way to determine if dietary CLA may also be appropriate for prevention of breast cancer in younger women. Dr. Ip noted that no toxicities have been associated with CLA in any of the human or animal studies performed to date, but she cautioned that additional clinical research is needed to establish its safety, effectiveness, and appropriate dose levels.
Soy Compound Reduces Mammary Tumor Numbers by More Than 50% in Rats
Rats fed a diet containing genistein, a soy compound, before exposure to a potent cancer-causing drug, developed at least 50% fewer mammary tumors than control rats, investigators reported today. The study shows that the protective effects were associated with genistein given at specific life stages: prepuberty alone and prepuberty plus adulthood. At the prenatal and adult-only stages, a genistein containing diet had no meaningful effect.
"We think that genistein, like hormones of pregnancy, protects against cancer by speeding up the differentiation process. Because only undifferentiated cells can become cancerous if exposed to a carcinogen, the faster cells differentiate, the fewer undifferentiated cells there are to be susceptible to malignant transformation," explained Coral Lamartiniere, Ph.D., Department of Pharmacology and Toxicology at the University of Alabama at Birmingham. All genistein-fed animals displayed elevated levels of beta-casein, a marker of cell differentiation.
The researchers also concluded that at the prepubertal stage of development, genistein actually programs breast cells against cancer by affecting certain hormone receptors and signaling pathways. According to Dr. Lamartiniere, the prepubertal stage in rats is comparable to the preadolescent and adolescent stage in humans. The rats were all females of a strain well established as a good model of breast cancer.
In this study of dietary genistein, rats in treatment groups of 25-30 per group were fed 25mg and 250 mg of genistein per kilogram diet - an amount resulting in blood levels in rats similar to blood levels in women who eat a high-soy diet. The carcinogen was administered on Day 50, and tumors appeared 40-60 days later.
Control rats developed an average of 8.9 tumors. By comparison, the prepubertal genistein group had an average of 4.3 tumors (51.7% fewer), and animals fed genistein at puberty and again as adults after exposure to the carcinogen averaged 2.8 tumors (68.6% fewer), indicating an added benefit. Two other laboratories have now produced similar results using slight variations in treatment with dietary genistein.
These findings are consistent with data from a retrospective analysis of a large case control study involving the Shanghai Cancer Registry, reported in 2001. That analysis, prompted by data from Dr. Lamartiniere's research, found a 50% lower incidence of breast cancer later in life for women who had a high-soy diet at ages 13-15.
"Era of Hope" is a forum for the presentation of research supported by the U.S. Department of Defense's Breast Cancer Research Program (BCRP), an unprecedented partnership between the military, scientists, clinicians, and breast cancer survivors. Since 1992, the BCRP has been working to prevent and cure breast cancer by fostering new directions in research, addressing underserved populations and issues, encouraging the work of new and young scientists and inviting the voice of breast cancer survivors to be heard in all aspects of the program. One of many congressional research programs managed by the U.S. Army Medical Research and Materiel Command, the BCRP has received more than $1.3 billion to date from Congress for innovative breast cancer research.
"Conjugated Linoleic Acid Modulation of Mammary Stromal Differentiation Contributes to its Chemopreventive Activity in Mammary Carcinogenesis"
MM Ip, PA Masso-Welch, C Ip, D Zangani
- General Session: Friday, September 27, 4:15 p.m.-5:45 p.m., Room 106
"Genistein Programming Against Breast Cancer"
CA Lamartiniere, J Wang
- General Session: Friday, September 27, 2:30 p.m.-4:00 p.m., Room 106