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The "Epidemic" of Breast Cancer in the U.S.--Determining the Factors

The "Epidemic" of Breast Cancer in the U.S.--Determining the Factors

It is widely accepted that the causation of cancer is the result of environmental exposures (including endogenous hormone exposure) and genetic susceptibility. Ultimately, to prevent breast cancer, we must understand both the environmental and genetic components.

As summarized by King and Schottenfeld, during the past 20 years of research, several risk factors and protective factors for breast cancer have been identified (Table 1). All of these factors can be understood as measures of the cumulative exposure of breasts to estrogen and, perhaps, progesterone. These ovarian hormones affect the rate of cell division and thus manifest their effect on the risk of breast cancer by causing proliferation of breast epithelial cells. Proliferating cells are susceptible to genetic errors during DNA replication, which, if uncorrected, can ultimately lead to a malignant phenotype.

Early menarche and late menopause maximize the number of ovulatory cycles and, therefore, the cumulative estrogen "dose" to the breast epithelium. Prolonged lactation and, more important, physical activity can reduce the number of ovulatory cycles. The primary source of estrogen in postmenopausal women is from the conversion of androstenedione to estrone in adipose tissue; thus, postmenopausal obesity increases the risk of breast cancer through increased production of estrogen. Obesity is also associated with decreased SHBG (sex hormone-binding globulin) production and increased proportions of free and albumin-bound estradiol, which are understood to be the biologically active estrogen [1]. In addition, alcohol appears to increase plasma estrogen levels.

The protective effect of early age at first birth is complex. During the first trimester of pregnancy, the level of free estradiol rises rapidly. However, as the pregnancy continues, prolactin and free estradiol levels lower, whereas SHBG levels rise, yielding a net overall benefit with respect to the endogenous estrogen profile, which permanently reduces the risk of breast cancer [2].

Further evidence of the crucial role of endogenous estrogens in the etiology of breast cancer is found in studies of serum and urine estrogen levels in low-risk and high-risk populations. Shimizu et al [3] reported higher levels of serum estrone and estradiol in postmenopausal white women in the United States than in postmenopausal women living in rural Japan. Bernstein et al [4] found higher serum estradiol levels in premenopausal cases than in controls in two concurrent studies in Shanghai and the United States, after carefully controlling for the day of the menstrual cycle. Furthermore, they showed that American controls had higher estradiol concentrations than their Shanghai counterparts. Higher levels of estrone and estradiol were also found in postmenopausal cases of breast cancer compared to controls in Los Angeles [5]. In a prospective study focusing on postmenopausal breast cancer, Toniolo et al [6] found that the highest quartiles of estrone, free estradiol, and albumin-bound estradiol were associated with a twofold to nearly fourfold increased risk of breast cancer, after adjusting for Quetelet index (a measure of body mass).

Genetic Susceptibility

Less has been learned about genetic susceptibility to breast cancer. However, remarkable advances in molecular biology and careful study of cancer-prone families have recently led to the identification of two breast cancer susceptibility genes, BRCA1 and BRCA2. As discussed by King and Schottenfeld, these genes may cause as much as 90% of breast and ovarian cancer in some families, but probably no more than 5% of all breast cancer in the United States is attributable to these two loci. Clearly, additional genes likely contribute to the risk of breast cancer. Much more common are multiple susceptibility genes, which have low absolute risk, but potentially high population attributable risk.

One such class of genes is that which codes for enzymes or receptors that control the metabolism and intracellular transport of estrogens. For example, the gene that codes for the enzyme 17- hydroxysteroid dehydrogenase (17-HSD), which acts in both the breasts and ovaries, converts estrone to the more active estradiol [2]. Another possible gene of importance, especially in postmenopausal women, is that which codes for aromatase, which converts androstenedione to estrone in adipose tissue [1].

Studying mutations and polymorphisms in these and other genes involved in estrogen metabolism will further our understanding of breast cancer. Individual differences in estrogen metabolism attributed to genetic polymorphisms and mutations should help us to identify women who may be at greater risk of breast cancer from certain exposures, such as exogenous estrogen, compared to other women who may be relatively genetically "insensitive" to the same exposure.

Explicit epidemiologic studies of gene-cancer relationships must be conducted to further our understanding of breast cancer etiology, control, and, ultimately, prevention. Although these types of investigations are still in their infancy, it is time to begin to capitalize on the rapid advancement of molecular biology techniques and to integrate them into epidemiologic studies.


1. Bernstein L, Ross RK: Endogenous hormones and breast cancer risk. Epidemiol Rev 15:48-65, 1993.

2. Henderson BE, Bernstein L: Endogenous and exogenous hormonal factors. In: Harris JR, Morrow M, Lippman ME, Helman S, eds. Diseases of the Breast, pp 185-200. Philadelphia, Lippincott-Raven, 1996.

3. Shimizu H, Ross RK, Bernstein L, et al: Serum oestrogen levels in postmenopausal women: Comparison of American whites and Japanese in Japan. Br J Cancer 62:451-453, 1990.

4. Bernstein L, Yuan JM, Ross RK, et al: Serum hormone levels in premenopausal Chinese women in Shanghai and white women in Los Angeles: Results from two breast cancer case-control studies. Cancer Causes Control 1:51-58, 1990.

5. Bernstein L, Ross RK, Pike MC, et al: Hormone levels in older women: A study of postmenopausal breast cancer patients and healthy population controls. Br J Cancer 61:298-302, 1990.

6. Toniolo PG, Levitz M, Zeleniuch-Jacquotte A, et al: A prospective study of endogenous estrogens and breast cancer in postmenopausal women. J Natl Cancer Inst 87:190-197, 1995.

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