Endogenous hormone metabolism as an exposure marker in breast cancer chemoprevention studies.

There is overwhelming evidence that alterations in endogenous hormone metabolism--as a form of endogenous exposure-may be an important metabolic risk factor for the development of breast cancer. This chapter reviews current theories and major epidemiological findings that link endogenous hormones (sex steroids and their metabolites, but also insulin, and insulin-like growth factor-I (IGF-I)) to breast cancer risk. Knowledge about these metabolic risk factors can be used to identify women at increased risk of breast cancer, who might benefit most from chemoprevention. In addition, modification of high-risk endocrine profiles may itself become a central target of chemoprevention. Possible intervention strategies include improvement of insulin sensitivity, reducing concentrations of IGF-I in blood and breast tissue, reducing ovarian overproduction of androgens, inhibiting the activity of aromatase and other enzymes involved in estrogen formation within the breast, and modifying estrogen metabolism within the breast (e.g., decreasing 16alpha- and 4alpha-hydroxylation, and increasing O-methylation of catecholestrogens). Several of these possible strategies are illustrated with examples of chemopreventive agents currently in use or proposed for use to prevent breast cancer.