A firm link between female reproductive history and increased risk of developing cancer in the breast and endometrium has been established from epidemiological studies (1-4). The longer women are exposed to estrogens, either through early menarche and late menopause and/or through estrogen replacement therapy, the higher is the risk of developing certain hormone-dependent cancers. It used to be thought that the purported benefits of estrogen replacement therapy, which included the relief of menopausal symptoms, decrease in coronary heart disease, osteoporosis, stroke, and Alzheimer’s disease, justified the use of long-term estrogen replacement therapy. However, the release of the initial results from the Women’s Health Initiative Study in July 2002 cast serious doubt on this paradigm for the treatment of post-menopausal women (5). The estrogen plus progestin arm was halted three years early due to significant increases in breast cancer, coronary heart disease, stroke, and pulmonary embolism, with more recent data suggesting an increase in vascular dementia in women over 65 on estrogen replacement therapy (6). In 2004, the estrogen arm was halted because of increased incidence of stroke (7). A recent analysis of data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) registries showed that age-adjusted incidence rate of breast cancer fell sharply (6.7%) in 2003 compared to 2002, which seemed to be related to the drop in the use of HRT (8). Finally, a reanalysis of nine prospective studies has shown that exposure to estrogens is associated with an increase in breast cancer risk with evidence of a dose-response relationship (9). These troubling findings highlight the urgent need for a full understanding of all the deleterious effects of estrogens including their potential to initiate and/or promote the carcinogenic process.
The mechanisms of estrogen carcinogenesis are not well understood. The central hypothesis of this review is that the formation of electrophilic/redox active quinones is an important mechanism of carcinogenesis for estrogens (Scheme 1, using the equine estrogen equilenin as an example). o-Quinones and quinone methides are known metabolites of estrogens and they have been shown to cause alkylation and/or oxidative damage to cellular proteins and DNA (2, 10-13). In addition, our data strongly suggests that estrogen receptors (ERs) appear to play a major role in catechol estrogen-induced DNA damage (14, 15). Binding and/or alkylation of ERs by the o-quinones generates a highly redox active “Trojan horse” which selectively targets estrogen sensitive genes. The long-range goal is to develop a better understanding of these reactive intermediates in vivo which will allow the rational development of estrogen replacement therapies that maintain the beneficial properties of estrogens without generating genotoxic species.