Differential Interactions of Estradiol Metabolites with the Estrogen Receptor: Genomic Consequences and Tumorigenesis

The incidence of breast cancer in the human has been rising and is now such that one out of nine women will develop the disease in her lifetime and one out of 18 will die from it. Ample epidemiological evidence indicates that the incidence is not a random process, but that both exogenous and endogenous factors enhance the risk for breast cancer (1). A prime candidate among the endogenous factors influencing the risk for the disease is the female sex hormone estradiol and its metabolites. While animal evidence is unequivocal that estrogens play an essential role in the etiology of breast tumors (2), in humans the evidence of estrogen participation in breast cancer incidence is indirect but nevertheless convincing (3). Numerous studies have, therefore, been directed to unearth a difference in the estrogen secretion and metabolism in breast cancer patients relative to unaffected controls, but these efforts have been frustrated by the technical difficulties of measuring the very low levels of these hormones which also undergo complex patterns of excretion and conjugation in body fluids. A second, and possibly more important factor why no consistent differences have become apparent is the likelihood that the initiation of the breast tumor, or carcinogenesis, precedes its clinical diagnosis by a period of 20 or more years. Hence analysis of the estrogen milieu at the time of diagnosis may reveal little about its features at the time of carcinogenesis. This time lag issue has been addressed in a prospective as well as retrospective manner.