For women concerned about breast cancer, looking over the list of known risk factors can be cause for frustration, as few of the stronger risks appear to be modifiable. But this may change as more is learned about the role of exercise in preventing breast cancer.

A growing body of research indicates that the levels of hormones produced by the body can be modified by physical activity. While a woman cannot change her age at menarche or menopause, and may not have children or breast feed - all factors which affect the levels of ovarian hormones a woman is exposed to over her lifetime - many researchers believe that she can reduce her exposure to these hormones through exercise.

Ovarian hormones including estrogen and progesterone, for example, are necessary for a woman's reproductive and overall health, but they also stimulate breast cells to proliferate, which can increase the accumulation of genetic mutations and potentially lead to tumor formation.

"Our theory is that the accumulative number of ovulatory menstrual cycles a woman experiences is predictive of her breast cancer risk," explains Dr. Leslie Bernstein, professor of cancer etiology at City of Hope Comprehensive Cancer Center.

She and her colleagues have been involved in the California Teachers Study (CTS) since 1995, which enrolled 133,479 current and retired teachers and school administrators in the state of California to prospectively study potential causes of an excess incidence of breast and other cancers observed in this population.

Last year the CTS investigators found that the risk of invasive breast cancer was inversely associated with long-term strenuous physical activity - women who averaged more than 5 hours a week of strenuous physical activity between high school and their current age (or age 54 if 55 or older) had a significantly reduced risk compared to women who averaged less than half an hour of strenuous physical activity a week during the same period of life.

Unexpectedly, neither strenuous nor moderate long-term physical activity was associated with reduced risk of estrogen receptor (ER)-positive breast cancer, but women who participated in long-term strenuous physical activity had a 55 percent reduction in risk of ER-negative breast cancer, and women who participated in long-term moderate physical activity had a 47 percent reduction in risk.

While drugs such as tamoxifen and raloxifene can help prevent the formation of ER-positive breast cancer, no such agents currently exist that can help prevent ER-negative cancer, making interventions to reduce the risk of ER-negative cancer "critically important," says Dr. Bernstein.

Investigators from NCI's Division of Cancer Epidemiology and Genetics (DCEG) recently obtained similar results from their National Institutes of Health-American Association of Retired Persons (AARP) Diet and Health Study, another prospective cohort study begun in 1995. They examined current physical activity among women aged 50 to 71 at the beginning of the study and evaluated physical activity in relation to breast cancer diagnosis according to hormone-receptor status. Their results were consistent with the CTS, showing that higher levels of exercise decreased the risk of ER-negative breast cancer.

Other studies are needed to tell "whether the apparent protective effect of physical activity on breast cancer risk observed was due to a direct effect of exercise on hormone levels," says Dr. Michael Leitzmann, formerly of DCEG and lead investigator on the study. Other factors may also affect how exercise modulates breast cancer risk, including decreased levels of circulating insulin and insulin-like growth factors, reduction of chronic inflammation, and modulation of the immune response.

In addition to questions about mechanism, it's not yet clear how much exercise is needed for a protective effect, nor at what age exercise may have the greatest benefit on breast cancer risk. However, recent data from the Nurses' Health Study II (NHSII) suggest that beginning regular exercise early in adolescence and young adulthood may be important for the prevention of premenopausal breast cancer.

Investigators from the NHSII examined lifetime physical activity beginning at age 12 in 64,777 premenopausal women, and found a 23 percent reduction in risk for premenopausal breast cancer among women who exercised, on average, an equivalent of 3.25 hours a week of running or 13 hours a week of walking during adolescence. "Long-term, sustained activity showed the greatest benefit," says Dr. Graham Colditz, professor of medicine at Washington University in St. Louis and senior author of the study.

However, high levels of physical activity during ages 12 to 22 contributed most strongly to the observed reduction in risk in the NHSII study. Researchers speculate that this may have something to do with a vulnerable period in breast development. "From the time of early onset of puberty until first pregnancy, that's a time of maximal risk accumulation in terms of the breast not being fully developed, and that can be a period of great hormonal irregularity for many reasons beyond pubertal growth and maturation, including weight change, physical activity changes, dietary changes, and alcohol exposures," explains Dr. Rachel Ballard-Barbash, associate director of the Applied Research Program in NCI's Division of Cancer Control and Population Sciences.

"But most studies suggest that even if you weren't physically active at one period of life, that becoming physically active at any point in your life is beneficial," she continues. "It's just as important for women to be conscious of their overall health as it is to be conscious of things that may have a specific influence on their breast health."

—Sharon Reynolds