2,3,7,8-Tetrachlorodibenzo-p-dioxin has both pro-carcinogenic and anti-carcinogenic effects on neuroendocrine prostate carcinoma formation in TRAMP mice.

It is well established that the prototypical aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can both cause and protect against carcinogenesis in non-transgenic rodents. But because these animals almost never develop prostate cancer with old age or after carcinogen exposure, whether AHR activation can affect cancer of the prostate remained unknown. We used animals designed to develop this disease, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, to investigate the potential role of AHR signaling in prostate cancer development.

The selective aryl hydrocarbon receptor modulator 6-methyl-1,3,8-trichlorodibenzofuran inhibits prostate tumor metastasis in TRAMP mice.

The aryl hydrocarbon receptor (AhR) is a basic-helix-loop-helix transcription factor that binds halogenated aromatic hydrocarbons, polycyclic aromatic hydrocarbons, and endogenous compounds. We previously reported that AhR null (Ahr(-/-)) transgenic adenocarcinoma of the mouse prostate (TRAMP) mice on a C57BL/6J background develop prostate tumors with much greater frequency than AhR wild-type (Ahr(+/+)) TRAMP mice, suggesting that the AhR has tumor suppressor properties. Because AhR signaling pathway inactivation increased susceptibility to prostate tumorigenesis, we tested the hypothesis that a selective AhR modulator (SAhRM), 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF), can protect against prostate tumorigenesis.

WNT5A selectively inhibits mouse ventral prostate development.

The establishment of prostatic budding patterns occurs early in prostate development but mechanisms responsible for this event are poorly understood. We investigated the role of WNT5A in patterning prostatic buds as they emerge from the fetal mouse urogenital sinus (UGS). Wnt5a mRNA was expressed in UGS mesenchyme during budding and was focally up-regulated as buds emerged from the anterior, dorsolateral, and ventral UGS regions.

Retinoic acid induces prostatic bud formation.

Formation of prostatic buds from the urogenital sinus (UGS) to initiate prostate development requires localized action of several morphogenetic factors. This report reveals all-trans-retinoic acid (RA) to be a powerful inducer of mouse prostatic budding that is associated with reciprocal changes in expression of two regulators of budding: sonic hedgehog (Shh) and bone morphogenetic protein 4 (Bmp4). Localization of retinoid signaling and expression of RA synthesis, metabolism, and receptor genes in the UGS on embryonic days 14.

The aryl hydrocarbon receptor (AhR) inhibits vanadate-induced vascular endothelial growth factor (VEGF) production in TRAMP prostates.

Hypoxia-inducible factor-1 alpha (HIF-1alpha) and aryl hydrocarbon receptor nuclear translocator (ARNT) are basic helix-loop-helix/per-arnt-sim (PAS) family transcription factors. During angiogenesis and tumor growth, HIF-1alpha dimerizes with ARNT, inducing expression of many genes, including vascular endothelial growth factor (VEGF). ARNT also dimerizes with the aryl hydrocarbon receptor (AhR).

The aryl hydrocarbon receptor inhibits prostate carcinogenesis in TRAMP mice.

The aryl hydrocarbon receptor (AhR) is a transcription factor that mediates the inhibitory effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on prostate growth and also modulates normal prostate development. This is evidenced by AhR null mice (Ahr-/-) having smaller dorsolateral and anterior prostates, even though all prostate lobes remain histologically normal. To test the hypothesis that loss of the AhR increases the rate of prostate carcinogenesis, the incidence of macroscopic prostate tumors was determined in Ahr+/+, Ahr+/- and Ahr-/- C57BL/6J transgenic adenocarcinoma of the mouse prostate (TRAMP) mice at 35, 70, 105, 140, 175 and 210 days of age.

In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: effects on the prostate and its response to castration in senescent C57BL/6J mice.

In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure inhibits ventral, dorsolateral, and anterior prostate development in C57BL/6 mice. To determine if prostatic abnormalities persist into senescence, mice born to dams given TCDD (5 mug/kg, po) or vehicle on gestation day 13 were examined at 100 and 510 days of age. Half the mice were castrated ten days prior to necropsy in order to assess androgen dependence, while the remaining mice were sham castrated.

Dynamic profiling of estrogen receptor and epidermal growth factor signaling in the uteri of genistein- and estrogen-treated rats.

The pharmacokinetics and time course actions of the soy isoflavone, genistein, and estradiol benzoate (EB) on sex steroid and growth factor signaling were compared in the rat uterus. Following one s.c.

Dietary diethylstilbestrol but not genistein adversely affects rat testicular development.

Isoflavones, including genistein, contribute to the health benefits of a soy diet. However, the estrogenic activity of genistein suggests that there may be adverse effects on reproductive tract development. We investigated the potential of exposure to genistein (250 and 1000 mg/kg diet) and the synthetic estrogen and known male reproductive toxicant, diethylstilbestrol (DES, 75 micro g/kg diet) from d 21 to d 35 to alter rat testicular development.

Genistein alters growth but is not toxic to the rat prostate.

The mortality of clinical prostate cancer is lower in Asian populations than in American or European men. Asian men typically consume more soy than their Western counterparts, leading to the investigation of individual components, particularly phytoestrogens, as protective factors against prostate cancer. Genistein, the predominant isoflavone in soy, has been reported to reduce the incidence of prostate cancer in animal models, but the underlying biological action remains to be elucidated.

Genistein action in the prepubertal mammary gland in a chemoprevention model.

A diet high in soy is associated with many health benefits, including reduced incidence of breast cancer. The soy phytoestrogen, genistein, is hypothesized to contribute to mammary chemoprevention via interaction with estrogen receptors (ERs) alpha and/or beta. These steroid signaling pathways are believed to exert control over proliferation and differentiation of the mammary gland by a complex bidirectional interaction with the epidermal growth factor (EGF) signaling pathway.

Genistein chemoprevention: timing and mechanisms of action in murine mammary and prostate.

We investigated the potential of genistein, the primary isoflavone of soy, to protect against breast and prostate cancers in animal models. For mammary cancer studies, Sprague-Dawley rats were fed AIN-76A diet plus minus 250 mg genistein/kg diet. Dimethylbenz[a]anthracene was administered by gavage at d 50 postpartum to induce mammary tumors.

Dietary genistein down-regulates androgen and estrogen receptor expression in the rat prostate.

The incidence of clinically manifested prostate cancer is higher in the United States and Europe than in Asian countries. One of the major differences in lifestyle between these populations is the diet, with Asians consuming a greater amount of soy. Soy and genistein, the predominant isoflavone found in soy, inhibit prostate tumor development in animal models.