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.