Etiology Of Breast Cancer

With colon cancer and increasingly lung cancer, breast cancer constitutes the trias of major cancers in females in Western industrialized countries. In these countries, the life-time risk of breast cancer is around 10% for women, and about 30% of them turn out to be lethal. Most breast cancers become apparent in women after their menopause, but a significant fraction is diagnosed earlier. In Western countries, the mean age at menopause is now «50 yrs, and menopause takes place in almost all women between 45 and 55. In females aged 40-60 years, breast cancer is the most frequent lethal cancer. In most countries, its incidence is rising, although the increase in mortality has been checked. There are several explanations for this phenomenon, invoking earlier detection and better treatment (^20.4). In any case, it is generally agreed that certain aspects of the Western life style favor the development of breast cancer. There is much less agreement on which aspects these are (Table 18.1).

Estrogen exposure: One risk factor can be summarized as the life-time length of exposure to estrogens. Earlier menarche, later menopause, and fewer (as well as later) pregnancies associated with the Western life-style all lengthen this period. Each change singly is associated with an increased risk of breast cancer. The underlying mechanism could be simply probabilistic. With prolonged exposure to estrogen and a longer period of proliferation cycles, the number of cells that can contract mutations is increased and initiated tumor cells get more time to expand. Specifically, strong signals enforce differentiation of breast ductal cells during pregnancy and others elicit extensive apoptosis of alveolar and ductal cells after weaning. These cycles may help to remove initiated tumor cells and act to 'purify' the tissue. Accordingly, a strong preventive effect is exerted by multiple pregnancies early in life with extended nursing periods.

A second, albeit not mutually exclusive explanation for the effect of estrogen exposure relates to the chemical structure of estrogens. Estrogens and their metabolites are phenolic compounds, after all (Figure 18.5). In particular, diphenolic estrogen metabolites can become partially oxidized to semiquinones which can react with macromolecules in the cell including DNA and induce mutations.

Table 18.1. Potential causes of human breast cancer

Potential factors causing breast cancer in humans * Length of exposure to estrogens Ionizing radiation

Genetic predisposition (BRCA1, BRCA2, others) Sedentary life style High-fat diet Alcohol

Tobacco smoking

* Several factors may interact, also synergistically.

Semiquinones can, moreover, initiate a process called quinone redox cycling that produces highly reactive oxygen species. So, estrogens may act as chemical carcinogens. If so, the risk of cancers in organs with high estrogen concentrations may strongly depend on the individual ability to metabolize estrogens and to deal with quinone adducts to DNA and redox cycling. Many genes involved in estrogen biosynthesis and metabolism are polymorphic, as are some of the relevant protective enzymes. An interaction between genes and environment is therefore strongly suspected (cf. 18.3).

Exposure to ionizing radiation: Here, too, gene-environment interactions are suspected. They are particularly clear in the case of inherited defects in the repair of DNA damage caused by ionizing radiation. For instance, certain carriers of mutations in the ATM gene may be at increased risk for breast cancer (^-3.4). The relationship between exposure to radiation and breast cancer risk becomes specifically relevant, when discussing prevention of breast cancer mortality by early detection. There are concerns that population screening by frequent mammography might put susceptible individuals at increased risk (^20).

High-fat diet: The breast cancer incidence in a country is clearly correlated to the content of fat, particularly of saturated animal fats, in the diet. The biological mechanisms that underlie this epidemiologically clear-cut correlation are not really understood. One hypothetical chain of events also invokes estrogens. The adipose tissue of postmenopausal women contains aromatase, a key biosynthetic enzyme for estrogens. So, high-fat diets may lead to overweight with expansion of adipose tissue leading to increased aromatase activity leading to continued production of estrogens after menopause with inappropriate growth stimulation of breast epithelial cells.

Genetic predisposition: The effects of all of the above factors may be dependent on genetic polymorphisms which modulate cancer risk in interaction with environmental factors. Polymorphisms in genes of steroid hormone metabolism, DNA repair (^3.4), cell protection (^3.5), and lipid metabolism, e.g. could all be relevant. While these polymorphisms may exert large effects on the overall incidence of breast cancer, they increase the risk only slightly for each individual woman and they are strongly dependent on other, notably environmental factors (^■2.3). In contrast, genetic factors predominate in the smaller fraction of (typically familial) cases that are caused by inherited mutations in one of a limited number of high-risk genes (—>18.3).

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