Etiologic Summary

Much is known about the behavioral factors that influence breast cancer risk, and the links between these factors and the pathophysiology of the disease are becoming clearer. Known and suspected risk factors are described in this article, grouped by reproductive, hormonal, nutritional, and other variables. Approximate strengths of association are also given for specific comparisons.

These comparisons are somewhat arbitrary, because many of these risk factors are continuous variables, and the relative risks depend on the levels chosen for comparison. For example, for age at menarche, 15 years has been compared with 11 years, but the relative risk would be stronger if age 17 were contrasted with age 11. Although most of these risk factors are established with a high degree of certainty, some - such as high prolactin levels, low physical activity, and low consumption of monounsaturated fat - require further research for confirmation.

Mechanisms linking confirmed and suspected risk factors to the development of breast cancer are known with varying levels of certainty. Early events involve mutations of breast stem cells. These mutations can be inherited (e.g., mutations in BRCA1, BRCA2, or the p53 gene) or acquired, such as by exposure to ionizing radiation. Little evidence exists that classic chemical carcinogens play an important role in human breast cancer by causing early mutations. Oxidative damage from endogenous metabolism is hypothesized to contribute to DNA damage, but the importance of this mechanism is difficult to quantify.

To the extent that oxidative damage is important, antioxidants in vegetables and fruits may account in part for the apparent protective effects seen with higher intake of these foods, and higher intake of monounsaturated fat results in cell structures that are less easily oxidized. Low availability of folic acid, which is exacerbated by high alcohol intake, leads to the incorporation of uracil rather than thymine into DNA and can also be a cause of mutations. Pregnancy appears to render the breast substantially less susceptible to somatic mutations, although the exact mechanisms are unclear; thus, earlier first pregnancies minimize the period of susceptibility. Vitamin A also plays a role in maintaining cell differentiation, but it may be that only quite low intakes are related to increased risk.

High endogenous estrogen levels are now well established as an important cause of breast cancer, and many known risk factors operate through this pathway. The additional contributions of cyclical estrogen exposure (as opposed to continuously high levels) and progestins are less clear, but available evidence suggests that progestins add to breast cancer risk. Factors that increase lifetime exposure to estrogens and progestins include early age at menarche, regular ovulation, and late menopause.

Lactation and overweight during young adult life result in anovulation, and this probably accounts for most of their protective effects. Extreme underweight also causes anovulation and would be expected to reduce risk, but direct evidence is lacking. Alcohol consumption increasesendogenous estrogen levels, and this may, at least in part, account for the observed increase in risk among regular drinkers. The increased risk of breast cancer among current or recent users of older high-dose oral contraceptives is also presumably due to their estrogenic (and possible progestational) effects.

After menopause, the major determinants of estrogen exposure are the amount of body fat and use of postmenopausal hormones; these are important risk factors for breast cancer. Increases in physical activity can delay the onset of menarche and can also reduce risk of breast cancer by helping to control weight gain and possibly by reducing ovulation and endogenous estrogen levels among premenopausal women.

Estrogens, by their mitotic effect on breast cells, appear to accelerate the development of breast cancer at many points along the progression from early mutation to metastasis and death. By increasing cell multiplication, estrogens may also increase the probability that DNA lesions become mutations.

Although earlier exposure to high estrogen levels during adolescence increases risk decades later, reduction in levels late in life abruptly reduces risk, whether this be by oophorectomy, cessation of postmenopausal hormones, or the administration of antiestrogens. Other growth factors in addition to estrogens, particularly IGF-I and prolactin, also appear to contribute to risk of breast cancer, but these relationships are less firmly established.

Although this broad outline of breast carcinogenesis is unlikely to change substantially with further research, many details are incomplete, and other contributing factors will probably be documented. For example, genetic polymorphisms yet to be identified are likely to contribute to variation in endogenous levels of, or responsiveness to, estrogens, IGF-I, and prolactin. Dietary and other behavioral determinants of these factors are incompletely defined. Also, other molecular mechanisms, such as DNA repair and apoptosis, are thought to be important in carcinogenesis in general, but the extent to which exogenous factors influence these processes in the context of human breast cancer is not known.

Walter C. Willett, Beverly Rockhill, Susan E. Hankinson, David J. Hunter and Graham A. Colditz

W. C. Willett: Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
B. Rockhill: Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts
S. E. Hankinson: Departments of Medicine and Epidemiology, Harvard Medical School and Harvard School of Public Health, Boston Massachusetts
D. J. Hunter: Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachussetts
G. A. Colditz: Department of Medicine, Harvard Medical School, Boston, Massachussetts


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