Reproductive Hormones

During the 1990s, a series of landmark prospective epidemiologic studies were published showing that a very important and reliable predictor of breast cancer risk is the amount of circulating estradiol in the blood of both pre- and postmenopausal women. In fact, this is the best single predictor of risk, said Brian Henderson, University of Southern California. How this risk factor accounts for increased risk of breast cancer is a subject of intense research.

A very important and reliable predictor of breast cancer risk is the amount of estradiol in the blood of both pre- and postmenopausal women

Brian Henderson

Henderson described a long-standing focus on the role of sex steroids in the etiology of breast cancer, especially related to stimulation of the breast by estrogen and, more recently, progestin. This focus has been driven by the premise that estrogen and progestin are the primary determinants of cell proliferation in breast epithelium and that cell proliferation is a prerequisite for many of the genetic changes necessary for cell transformation to a malignant phenotype. The strong and consistent association between a woman’s menstrual history and breast cancer risk implicates lifetime exposure to sex steroid hormones as a major factor in the causation of breast cancer.

Recent epidemiologic studies have implicated estrogens more directly, by showing that circulating levels of the biologically most potent estrogen, estradiol (E2), are significantly higher in breast cancer patients compared to normal controls. Moreover, said Henderson, plasma estrogen levels differ by racial–ethnic group and these differences appear to contribute to racial–ethnic variation in breast cancer rates. In addition, exogenous exposure to these steroids, as combined estrogen and progestin replacement therapy, also substantially increases the risk of breast cancer.

In addition to the level of circulating hormones, the role of hormone replacement therapy and the age at menarche and fecundity also have a relationship to breast cancer. For example, in the late nineteenth century in Europe and the United States, there was a pattern of a late age at menarche, a short period of fecundity, and an early onset of menopause. By the early twentieth century, the age of menarche had decreased and the length of fecundity increased, not only in the West but elsewhere in the world, including post-World War II Asia. This has coincided with a dramatic increase in breast cancer rates over the last 50 years. The use of multiethnic cohort studies will begin to address the complex interplay between genetic and environmental risk factors according to Henderson.

To further understand these risk factors, Henderson and others have turned to genetics. The process of breast cancer is driven by ovarian steroid hormones, mainly estradiol and progesterone, and these result from a biosynthetic pathway that involves a series of enzymes encoded by genes (see Figure 5-1). It is in these



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