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

It is widely accepted that the causation of cancer is the resultof 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 yearsof research, several risk factors and protective factors for breastcancer have been identified (Table 1). All of these factors canbe understood as measures of the cumulative exposure of breaststo estrogen and, perhaps, progesterone. These ovarian hormonesaffect the rate of cell division and thus manifest their effecton the risk of breast cancer by causing proliferation of breastepithelial cells. Proliferating cells are susceptible to geneticerrors during DNA replication, which, if uncorrected, can ultimatelylead to a malignant phenotype.

Early menarche and late menopause maximize the number of ovulatorycycles and, therefore, the cumulative estrogen "dose"to the breast epithelium. Prolonged lactation and, more important,physical activity can reduce the number of ovulatory cycles. Theprimary source of estrogen in postmenopausal women is from theconversion of androstenedione to estrone in adipose tissue; thus,postmenopausal obesity increases the risk of breast cancer throughincreased production of estrogen. Obesity is also associated withdecreased SHBG (sex hormone-binding globulin) production and increasedproportions of free and albumin-bound estradiol, which are understoodto be the biologically active estrogen [1]. In addition, alcoholappears 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 estradiolrises rapidly. However, as the pregnancy continues, prolactinand free estradiol levels lower, whereas SHBG levels rise, yieldinga net overall benefit with respect to the endogenous estrogenprofile, which permanently reduces the risk of breast cancer [2].

Further evidence of the crucial role of endogenous estrogens inthe etiology of breast cancer is found in studies of serum andurine estrogen levels in low-risk and high-risk populations. Shimizuet al [3] reported higher levels of serum estrone and estradiolin postmenopausal white women in the United States than in postmenopausalwomen living in rural Japan. Bernstein et al [4] found higherserum estradiol levels in premenopausal cases than in controlsin two concurrent studies in Shanghai and the United States, aftercarefully controlling for the day of the menstrual cycle. Furthermore,they showed that American controls had higher estradiol concentrationsthan their Shanghai counterparts. Higher levels of estrone andestradiol were also found in postmenopausal cases of breast cancercompared to controls in Los Angeles [5]. In a prospective studyfocusing on postmenopausal breast cancer, Toniolo et al [6] foundthat the highest quartiles of estrone, free estradiol, and albumin-boundestradiol were associated with a twofold to nearly fourfold increasedrisk of breast cancer, after adjusting for Quetelet index (a measureof body mass).

Genetic Susceptibility

Less has been learned about genetic susceptibility to breast cancer.However, remarkable advances in molecular biology and carefulstudy of cancer-prone families have recently led to the identificationof two breast cancer susceptibility genes, BRCA1 and BRCA2. Asdiscussed by King and Schottenfeld, these genes may cause as muchas 90% of breast and ovarian cancer in some families, but probablyno more than 5% of all breast cancer in the United States is attributableto these two loci. Clearly, additional genes likely contributeto the risk of breast cancer. Much more common are multiple susceptibilitygenes, which have low absolute risk, but potentially high populationattributable risk.

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

Studying mutations and polymorphisms in these and other genesinvolved in estrogen metabolism will further our understandingof breast cancer. Individual differences in estrogen metabolismattributed to genetic polymorphisms and mutations should helpus to identify women who may be at greater risk of breast cancerfrom certain exposures, such as exogenous estrogen, compared toother women who may be relatively genetically "insensitive"to the same exposure.

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

References:

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

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

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

4. Bernstein L, Yuan JM, Ross RK, et al: Serum hormone levelsin premenopausal Chinese women in Shanghai and white women inLos 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 olderwomen: A study of postmenopausal breast cancer patients and healthypopulation controls. Br J Cancer 61:298-302, 1990.

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