Sex steroids and prostate carcinogenesis: integrated, multifactorial working hypothesis.

Abstract

Androgens are thought to cause prostate cancer, but there is little epidemiological support for this notion. Animal studies, however, demonstrate that androgens are very strong tumor promotors for prostate carcinogenesis after tumor-initiating events. Even treatment with low doses of testosterone alone can induce prostate cancer in rodents. Because testosterone can be converted to estradiol-17beta by the enzyme aromatase, expressed in human and rodent prostate, estrogen may be involved in prostate cancer induction by testosterone. When estradiol is added to testosterone treatment of rats, prostate cancer incidence is markedly increased and even a short course of estrogen treatment results in a high incidence of prostate cancer. The active testosterone metabolite 5alpha-dihydrotestosterone cannot be aromatized to estrogen and hardly induces prostate cancer, supporting a critical role of estrogen in prostate carcinogenesis. Estrogen receptors are expressed in the prostate and may mediate some or all of the effects of estrogen. However, there is also evidence that in the rodent and human prostate conversion occurs of estrogens to catecholestrogens. These can be converted to reactive intermediates that can adduct to DNA and cause generation of reactive oxygen species, and thus estradiol can be a weak DNA damaging (genotoxic) carcinogen. In the rat prostate DNA damage can result from estrogen treatment; this occurs prior to cancer development and at exactly the same location. Inflammation may be associated with prostate cancer risk, but no environmental carcinogenic risk factors have been definitively identified. We postulate that endogenous factors present in every man, sex steroids, are responsible for the high prevalence of prostate cancer in aging men, androgens acting as strong tumor promoters in the presence of a weak, but continuously present genotoxic carcinogen, estradiol-17beta.

• Authors: Maarten C Bosland
• Journal: Annals of the New York Academy of Sciences (Ann N Y Acad Sci) Vol. 1089 Pg. 168-76 (Nov 2006) ISSN: 0077-8923 [Print] United States
• PMID: 17261765 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Gonadal Steroid Hormones
• Receptors, Estrogen

Topics

• Animals
• Cell Transformation, Neoplastic (genetics, metabolism)
• DNA Damage
• Gonadal Steroid Hormones (metabolism)
• Humans
• Male
• Prostate (metabolism, pathology)
• Prostatic Neoplasms (etiology)
• Rats
• Receptors, Estrogen (metabolism)