Breast cancer is a disease of enormous public health importance. According to the World Health Organization’s International Agency for Research on Cancer, breast cancer is now the most common form of cancer inwomen in the world. Rates of new cases are highest in industrial nations but are rising rapidly in some developing countries (1). In those few developed countries where widespread screening programs have recently become routine, some of the growth in incidence reflects improved detection by mammography, which can spot small breast tumors years before they would otherwise be detected. Although increased use of mammography can explain part of the increase in new cases in the United States and a few other developed countries, it cannot account for the recent, substantial increases in certain regions in Central Europe and Asia where no screening is conducted (2).

For more than three decades, scientists have consistently identified a number of risk factors that are generally believed to account for up to 40 percent of all cases of breast cancer. Among the established risk factors for breast cancer are: having menstrual periods that begin before age 12 and end after age 55, having no children or bearing children late in life, not nursing children, early and repeated exposures to relatively high doses of radiation, obesity after menopause, and a family history of breast cancer occurring in a close relative before age 40 (3). Other factors are suspected of increasing risk, although the data are less clear. These include: drinking alcohol daily, lack of vigorous exercise, low intake of vitamin D and fiber, active and passive smoking, and living near chemical facilities(4).

Despite the continued public attention to inherited breast cancer genes, fewer than 1 in 10 cases develops in a woman born with defects in the major breast cancer genes identified thus far—BRCA1, BRCA2, and ATM (5). Breast cancer, like all cancers, is thought to arise from a multistep process that involves sequential or simultaneous damage to several genes that control cell growth and maturation. Genetic damage can also occur when a cell miscopies its own DNA during cell division and fails to repair such mistakes. Metabolic differences in the way the body processes compounds that are affected by genetic factors can also affect the risk of cancer developing (6).

So, although certain risk factors for breast cancer, such as age at menarche, diet, and genetic predisposition, have been well known for years, many breast cancer cases occur in women with no known risk factors for disease (7). Scientists cannot explain why there are more new cases of breast cancer today.  However, a growing and complex array of evidence suggests that the general external environment—including behavior, diet, and physical and chemical exposures—plays a major role in fostering breast cancer. The general environment can induce breast cancer by two distinct mechanisms. Environmental exposures may damage genes directly or they may affect the overall production of growth-regulating hormones, such as estrogen, progesterone, and other such naturally produced substances (8).

Timing of exposure may be just as important as the degree of exposure to one or more of these risk factors in the development of disease, with exposures that occur prenatally being especially important.

Further evidence that environmental factors generally play a role in the development of breast cancer comes from the observations of considerable geographic variation in breast cancer cases both among and within ethnic groups. Studies have shown that Asian women living in the United States have higher rates of breast cancer than women living in their countries of origin (9).

Abundant evidence exists that a woman’s cumulative exposure to estrogen plays a role in increasing breast cancer risk. The longer a woman is exposed to estrogen over the course of her lifetime, the greater her risk for developing breast cancer. Women who start menstruating at an earlier age and enter menopause at a late age, for example, are more vulnerable to breast cancer than women who are menstrual for a shorter period of time. Reduction of estrogen by surgical removal of ovaries can lower cancer risk substantially; breast-feeding, which lowers cumulative estrogen exposure by disrupting regular menses, also reduces the risk of breast cancer somewhat (10). In addition, women who have toxemia during pregnancy have lower hormone levels. One recent study suggests that their daughters have a reduced risk of breast cancer, possibly because their developing breast cells were subjected to lower prenatal levels of circulating hormones (11).

How might estrogens and other hormones be affecting the risk of breast cancer? Hormones, especially those that are not bound and excreted rapidly through normal metabolism, are thought to foster the growth of genetically damaged breast cells, causing them to develop into clinically significant cancers. Those periods when cells are rapidly dividing, as in the prenatal period and during puberty, are also times of greater vulnerability to genetic damages that can cause disease, because repair mechanisms may not be up to speed at the rate of cell growth. Studies suggest that elevated prenatal estrogen exposure affects breast cancer risk in offspring, perhaps by permanently affecting the sensitivity of breast cells to estrogen.

Such evidence of the role of naturally occurring hormones in cancer risk has led to the hypothesis that synthetic hormones could be involved as well. Over the past three decades, several lines of evidence have converged indicating that a number of commonly used synthetic compounds can modify or mimic the actions of natural estrogen in the body. (See Box on hormone mimics in Chapter 2.) Some of these hormone-mimicking compounds may be beneficial, such as those generally found in plants and fish. In contrast, other hormone-mimicking compounds appear to be generally harmful, such a those often found in pesticides, plastics, and fuels. Experimental, wildlife, and some human studies have found higher levels of some of these damaging compounds in organisms with altered hormonal functioning or other health problems, including developmental and behavioral defects (12).

Based on these observations, my colleagues at the Strang–Cornell Cancer Research Laboratory in New York City and I have hypothesized that these same hormone disrupting environmental exposures can play a role in the development of breast cancer, if they perturb the effects of natural estrogen. We theorize that certain of these synthetic xenoestrogens may increase the risk of breast cancer by adversely affecting the metabolism of estrogen, while other xenoestrogens in plants such as soy may protect against the disease. Natural estrogens and xenoestrogens can lead to breast cancer through the same mechanism. Both the body’s own natural estrogen as well as xenoestrogens can bind to estrogen receptors and alter how uch and what types of estrogen the body produces. Estradiol, the maintype of estrogen generated by women, is metabolized in the body into different forms that have markedly different effects in the body. There are thought to be “good” and “bad” forms of these estrogen metabolites. The good estrogen appears to promote cell repair and prevent cancer from arising by enhancing protective factors in the cell cycle that discourage cancer. In contrast, the bad estrogen appears to stimulate cancer-causing damage of protective genes and to increase overall amounts of unbound hormones, either one of which can prompt the accelerated growth of breast cells. Such enhanced growth increases the chance that genetic damage will occur and be sustained (13).

Animal and human studies suggest that high levels of the bad estrogen are tied to an increased risk of breast cancer (14).

While evidence for this hypothesis remains incomplete, experimental analyses have recently provided increased support for the theory. My colleagues at Strang and I found that human breast cancer cells had levels of the bad estrogen that were more than four times higher than those of normal breast cells. When organochlorine pesticides were added to breast cancer cells, the ratio of the amounts of bad to good estrogen significantly jumped (15). These pesticides, which tend to accumulate in fat cells may somehow have influenced the formation of different estrogen metabolites. These and other findings led us to postulate that exposures to certain xenoestrogens in the environment might account for some of the current rise in breast cancer incidence by increasing the ratio of bad and good estrogens in breast tissue. Several small studies conducted in the 1970s and 1980s found that women with higher levels of DDT metabolites in their blood had higher risks of breast cancer (16).

In contrast to these experimental studies of hormone-disrupting potential in environmental chemicals, human studies have not consistently found an association between some fat-seeking pesticide residues and breast cancer. Three recent studies have found no link between breast cancer risk and metabolites of DDT, a suspected estrogen mimic, in the body (17) (18). In these studies, however, both women with breast cancer and those with whom they were compared had levels of DDT pesticide metabolites that were nearly one sixth of those measured in the United States in the late 1960s (19). Moreover, in all these studies information could not be obtained in possible prenatal exposures to harmful xenoestrogens, nor on the history of long-term use or exposure to possible bad or good xenoestrogens, such as those in plants, fish, and fiber. In short, the jury is still out.

Documenting the role of potentially harmful xenoestrogens, such as some long-lived organochlorine pesticides, provides a major challenge to epidemiologic research. In part, this is because other contributing factors, both positive or negative, cannot be easily measured and may be of relatively greater importance. For instance, some relevant sources of bad estrogens for breast cancer could include exposures that occurred two or three decades earlier to widely used materials such as plastics, fuels, and pharmaceuticals, none of which could be detected years later because they do not accumulate in fat. Consistent with this idea is one recent study that found that post-menopausal women who had never breast-fed had a much higher risk of breast cancer compared with those who had breast-fed. Breast-feeding can release materials, such as organochlorines, from the breast into nursing infants.

References and notes

1. D.M. Parkin et al., eds., Cancer Incidence in Five Continents, Vol. VII, IARC (International Agency for Research on Cancer) Scientific Publications No. 143 (World Health Organization/IARC, Lyon, France), on CD-ROM.

2. Devra Lee Davis et al., "Environmental Influences on Breast Cancer Risk," Science and Medicine, Vol. 4, No. 3 (May-June 1997), p. 56.

3. M.P. Madigan et al., "Proportion of Breast Cancer Cases in the United States Explained by Well-Established Risk Factors," Journal of the National Cancer Institute, Vol. 87, No. 22 (1995), pp. 1681-1685.

4. Op. cit. 2, p. 58.

5. Op. cit. 2

6. Christine B. Ambrosone et al., "Cigarette Smoking, N-Acetyltransferase 2 Genetic Polymorphisms, and Breast Cancer Risk," Journal of the American Medical Association, Vol. 276, No. 18 (November 13, 1996), p. 1494.

7. Devra Lee Davis et al. "Recent Developments on the Avoidable Causes of Breast Cancer," in Preventive Strategies for Living in a Chemical World: A Symposium in Honor of Irving J. Selikoff, Annals of the New York Academy of Sciences, Vol. 837, Eula Bingham and David P. Rall, eds. (New York Academy of Sciences, New York, 1997), p. 514.

8. Ibid., p. 520.

9. Regina G. Ziegler et al., "Migration Patterns and Breast Cancer Risk in Asian-American Women," Journal of the National Cancer Institute, Vol. 85, No. 22 (November 17, 1993), pp. 1819-1827.

10. Op. cit. 2.

11. Anders Ekbom et al., "Intrauterine Environment and Breast Cancer Risk in Women: A Population-Based Study," Journal of the National Cancer Institute, Vol. 89, No. 1 (January 1, 1997), pp. 71–72.

12. Theo Colborn, Dianne Dumanoski, and John Peterson Myers, Our Stolen Future: Are We Threatening Our Fertility, Intelligence, and Survival? A Scientific Detective Story (Penguin Books, New York, 1996), pp. 47-67.

13. H. Leon Bradlow et al., "Effects of Pesticides on the Ratio of 16µ/2-Hydroxyestrone: A Biologic Marker of Breast Cancer Risk," Environmental Health Perspectives, Vol. 103, Supplement 7 (October 1995), pp. 147-150.

14. Devra Lee Davis et al., "Medical Hypothesis: Xenoestrogens as Preventable Causes of Breast Cancer," Environmental Health Perspectives, Vol. 101, No. 5 (October 1993), pp. 372-377.

15. Op. cit. 13.

16. Op. cit. 2, pp. 60-61.

17. David J. Hunter et al., "Plasma Organochlorine Levels and the Risk of Breast Cancer," The New England Journal of Medicine, Vol. 337, No. 18 (October 2, 1997), pp. 1253-1258.

18. Nancy Krieger et al., "Breast Cancer and Serum Organochlorines: A Prospective Study Among White, Black, and Asian Women," Journal of the National Cancer Institute, Vol. 86, No. 8 (April 20, 1994), pp. 589–599.

19. Op. cit. 17.