Potential Carcinogens from Steroid Hormones and Diethyl Stilbesterol (DES): Chemical Relationships between Breast, Ovarian and Prostate Cancers

With the exception of certain environmental causes of cancer like sun and occupational exposure (asbestos), many malignancies result from smoking, alcohol or dietary factors and others may be due to endogenous factors. While a large amount of research has focused on exogenous carcinogens both environmental and dietary, much less has been devoted to potential endogenous cancer initiators. In part, this stems from disbelief that naturallyoccurring compounds in man are carcinogens. Yet, reactive metabolites of the steroid hormones and related compounds have the potential to transform cellular nucleic acids and thereby initiate precursors to the malignant cell. An example is a potential metabolite of estradiol, which could lead to catechol estrogens, was shown to be as mutagenic as 3-methylcholantrene in 1980. And yet, no further research has been done to determine whether this proposed metabolite occurs in mammalian systems and if it does, whether it is a causative agent in breast or ovarian malignancies. Four important questions are: (1) if such metabolites arise in vivo, will tests show them to be carcinogenic?, (2) is there a dose-response relationship, in their causation of malignancies?, (3) what are the biological mechanisms, by which these compounds arise?, and (4) are these pathways perturbed in breast and prostate cancer patients, leading to excessive accumulation of these mutagens? These are merely four of many questions that must be addressed when examining potential endogenous carcinogens. Increasingly, there appears to be a genetic relationship between breast, ovarian and prostate cancers. Could that connection arise from chemical similarities between carcinogenic initiators derived from steroid hormones, their formation, incorporation into nuclear receptors as well as their rate of hydrolysis? These issues in addition to a clarification of the origin of such endogenous carcinogens will be explored. A testable hypothesis is proposed.