Combined treatment with testosterone (T) + estradiol-17beta (E2) induces prostate adenocarcinomas in 100 percent of NBL rats, and T alone a 40 percent incidence. This is the only model in which steroid hormones alone produce a high prostate cancer incidence; it offers opportunities to study the mechanisms whereby steroid hormones cause prostate cancer. We hypothesize that E2, either formed endogenously from T by the enzyme aromatase or exogenously administered, acts via a genotoxic mechanism that involves the generation of reactive oxygen species to produce prostate carcinomas in the presence of T, and that estrogen receptor (ER)-mediated mechanisms are not involved. To address the hypothesis and resolve some uncertainties about the model, the following specific aims are proposed.
Aim 1 : To establish whether E2 is an essential factor in the hormonal induction of prostate cancer by T, and whether it acts via a mechanism that is ER-independent; we will establish whether treatment with an aromatase inhibitor reduces or eliminates prostate cancer induction by T, and to demonstrate that antiestrogen treatment does not affect the tumor response.
Aim 2 : To determine whether induction of oxidative DNA damage and of prostate carcinomas by T and E2 are linked and, therefore, probably causally related; we will administer antioxidant vitamins (C and E) to T+E2-treated rats, which should reduce both prostate cancer induction and prostatic oxidative DNA damage (measured by formation of 8-hydroxydeoxyguanosine).
Aim 3 : To demonstrate that T+E2-induced carcinomas have the potential to metastasize and determine whether T+E2-induced peripheral prostate dysplasia can progress to cancer; we will determine whether lowering of the E2 dose or shortening of the E2 treatment duration, while continuing T administration, will sufficiently lower or delay pituitary tumor formation and prolong survival to allow progression of prostate carcinomas to the metastatic stage.
Aim 4 : To establish whether T+E2- induced prostate carcinomas are androgen-sensitive and their induction is androgen-dependent and prolactin-independent; we will test the response of prostate cancers transplanted into syngeneic rats to castration and determining the effect of castration of T+E2-treated rats at a time at which very small carcinomas have already formed.
| Bosland, Maarten C (2013) A perspective on the role of estrogen in hormone-induced prostate carcinogenesis. Cancer Lett 334:28-33 |
| Bosland, Maarten C (2006) Sex steroids and prostate carcinogenesis: integrated, multifactorial working hypothesis. Ann N Y Acad Sci 1089:168-76 |
| Condon, Mark S (2005) The role of the stromal microenvironment in prostate cancer. Semin Cancer Biol 15:132-7 |
| Milman, Harry A; Bosland, Maarten C; Walden, Paul D et al. (2002) Evaluation of the adequacy of published studies of low-dose effects of bisphenol A on the rodent prostate for use in human risk assessment. Regul Toxicol Pharmacol 35:338-46 |
| Bosland, M C (2000) The role of steroid hormones in prostate carcinogenesis. J Natl Cancer Inst Monogr :39-66 |
