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Breast Cancer: Susceptibility and the Environment.

It might seem odd that the National Institute of Environmental Health Sciences played a key role in the discovery of BRCA1, the first breast cancer gene, or that two years later, it took part in the successful international effort to identify the second such gene, BRCA2. But the institute's mission includes the study of susceptibility to environmental agents as well as the agents themselves.

Breast cancer appears to result from interactions between one's genes (susceptibility) and several possible environmental factors such as chemical pollutants, diet, and tobacco and alcohol use. Once these interactions are better understood, doctors will be able to design more effective strategies for the treatment and prevention of this disease, which kills more women than any other cancer except lung.

GENETIC HISTORY

Although hereditary breast cancer accounts for just 5 to 10 percent of cases, it can devastate a family, striking an aunt, mother and daughter before they are 45. This hereditary process is governed by genes, the units of inheritance that reside within the body's 23 pairs of chromosomes. Scientists have found two classes of genes that play critical roles in breast cancer development: Oncogenes control cell growth, and when activated through mutation, can trigger the production of cancerous cells. Tumor-suppressor genes act to prevent uncontrolled cell growth, and thus are able to keep cancers from forming. A person who has inherited a defective tumor-suppressor gene is without one of the body's best defenses against cancer.

Working with researchers from the University of Utah Medical Center and Myriad Genetics, NIEHS scientists in 1994 pinpointed the BRCA1 gene, a key suppressor gene that, when defective, is believed to be responsible for hereditary breast and ovarian cancer. Diagnostic tests can now identify women who have inherited bad copies of BRCA1 and BRCA2 genes. Institute researchers are currently developing mice that are genetically engineered to carry defective copies of these genes, which have been linked to inherited breast cancers. The researchers will compare the growth and development of these mice with that of normal mice, looking for differences that can unlock some of the secrets about how these genes work and what happens when they are damaged.

HORMONAL FACTORS

Most experts believe the female sex hormone estrogen influences breast cell growth by stimulating the release of proteins called growth factors. Growth factors then deliver a chemical signal to the breast cells that instructs them to divide and specialize, so that normal maturation of the breast can occur. Estrogens can also cause genetically altered breast cells to divide more rapidly than normal cells, resulting in a tumor. And, in animal studies, breast cancer-causing chemicals do not produce a significant increase in tumors unless estrogen is present.

CHEMICAL EXPOSURES

Recent studies have focused on pesticides and other chemicals called environmental estrogens because they "mimic" some of the properties of the female sex hormone. At the Mount Sinai School of Medicine in New York, investigators funded by NIEHS are comparing the levels of chemical residues in blood serum samples taken from breast cancer patients with those from control subjects with no history of the disease. One of their preliminary findings is that the breast cancer patients had significantly higher levels of DDE, the major break-down product of DDT. No significant association was found with PCBs, a substance once used as insulation in a great deal of machinery.

Additional studies funded under an agreement between NIEHS and the National Cancer Institute are also underway. One, the Northeast Mid-Atlantic Breast Cancer Program, is designed to explore pesticide exposure and breast cancer incidence in women who live in areas where breast cancer rates are higher than normal. Another, the Long Island (NY) Breast Cancer Study Project, will focus on possible links between breast cancer development and environmental exposures, including water and air pollutants, electric and magnetic fields, pesticides and other toxic chemicals, and hazardous and municipal wastes.

STAGE OF DEVELOPMENT

Puberty is marked by significant hormonal changes and steady growth of breast tissue. During this time of rapid cell division and differentiation, breast tissue may be especially sensitive to the effects of cancer-causing agents. Recent findings from both human and animal studies seem to support this theory. For example, when female rats whose breast epithelial cells are growing and maturing are exposed to aromatic hydrocarbons - chemicals that are typically found in exhaust fumes - virtually all of the rats develop breast cancer. Similarly, young Japanese females exposed to radiation from the atomic bomb had a greater risk of developing breast cancer than those who were exposed at an older age.

RISK FACTORS

Institute scientists have collaborated with investigators from the Tremin Trust Research Program to study the influence of menstrual and reproductive factors on the risk of developing breast cancer and other chronic diseases. The study revealed that women with a later age at natural menopause, as well as those with a later age at first pregnancy, had a slightly higher breast cancer risk, while women who had had four or more pregnancies had a significantly lower risk. In addition, the researchers found that women whose menstrual cycles averaged less than 26 days between bleedings had a 60 percent increase in breast cancer risk compared to women with longer cycles. Moreover, women with a greater cumulative lifetime number of menstrual cycles (more than 350 cycles) had about twice the risk as those with fewer cycles.

NIEHS grantees have shown that exposures to environmental estrogens at different ages can have very different effects on mammary gland development. This is especially true of genestein, a plant product that is a very good source of estrogen. When laboratory animals were fed genestein during neonatal or prepubertal periods, there was a temporary increase in cell growth and differentiation soon after administration. Once these same animals reached maturity, however, these effects were no longer evident. In fact, when these animals were exposed to known carcinogens as adults, they were less likely to develop breast cancer later in life than animals that had not received genestein. Researchers are conducting additional studies to determine whether genestein-rich foods, such as soybeans and other soy proteins, might protect against breast cancer!

(Media inquiries 919/541-2605 or 919/541-1993.)

NIEHS Fact Sheet # 11, BREAST CA, 8/97.

Our publications are not copyrighted and may be reproduced without permission. However, we do ask that credit be given to the National Institute of Environmental Health Sciences, National Institutes of Health.

FOR FURTHER INFORMATION on diseases related to the environment, see the NIEHS Home Page at http://www.niehs.nih.gov. Breast Cancer Answers at http://www.biostat.wisc.edu/bca/ includes a discussion of recommended steps for women found to carry defective BRCA1 or BRCA2 genes. The National Cancer Institute's cancer information service may be reached at 1/800/4-CANCER.
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Publication:Pamphlet by: National Institutes of Health
Article Type:Topic Overview
Date:Oct 13, 1998
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