Immunohistochemically demonstrated androgen receptor expression in the rat prostate during carcinogenesis induced by 3,2′-dimethyl-4-aminobiphenyl with or without testosterone

Shirai, Tomoyuki; Takahashi, Satoru; Mori, Toshio; Imaida, Katsumi; Futakuchi, Mitsuru; Ye, Shu Hua; Prins, Gail S.; Ito, Nobuyuki

doi:10.1016/1078-1439(96)00014-2

Cited by 8 publications

(6 citation statements)

References 13 publications

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“…We have previously reported that non-invasive ventral prostate carcinomas are androgen-dependent while invasive carcinomas of the anterior prostate or seminal vesicles are androgen-independent. 23,24) On the other hand, genistein and daidzein exhibited dose-dependent inhibition of the growth of androgen-independent PLS10 rat prostate cancer cells in vitro, and this is in keeping with previous reports on human prostate cancer cell lines. [25][26][27][28] The data suggest that the mechanism of action of genistin or daidzin depends on the androgen receptor signaling pathway at the low concentrations prevailing under in vivo conditions, while an androgen receptor-independent pathway may operate at the higher concentrations possible in vitro.…”

Section: Discussionsupporting

confidence: 90%

Suppressive Effects of Dietary Genistin and Daidzin on Rat Prostate Carcinogenesis

Kato

Takahashi

Chen

et al. 2000

Japanese Journal of Cancer Research

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High intake of phytoestrogens through soybeans and their products is thought to be associated with low incidences of prostate and/or breast cancer in Asian countries. Possible chemopreventive effects of genistin or daidzin on rat prostate carcinogenesis were therefore investigated. Male F344 rats were given 10 biweekly subcutaneous injections of 3,2′ ′ ′ ′-dimethyl-4-aminobiphenyl (DMAB) and then either genistin or daidzin in the diet at a concentration of 0.1% for 40 weeks. Other groups of rats given DMAB were treated with genistin or daidzin together with a high dose of testosterone propionate (TP). Both genistin and daidzin reduced the numbers of ventral prostate carcinomas (P < < < <0.05), with a tendency for decrease in incidence. Invasive carcinomas which developed in the anterior prostate and seminal vesicles with TP were, however, not influenced by the two isoflavones. Thus, the present data suggest that genistin and daidzin possess anti-cancer effects at relatively early stages of prostate cancer development, providing experimental support for epidemiological findings. Key words: Rats -DMAB -Prostate carcinogenesis -Genistin -DaidzinWhile prostate cancer is the most common internal neoplasm and the second leading cause of cancer death in men in the United States, 1) mortality in Japan from this cause is only two-ninths of that in the United States. 2)Intake of large amounts of soybeans and their products rich in isoflavones, such as genistin and daidzin, is believed to play a role in this difference.3) The daily consumption of isoflavones in the diet by Japanese people is estimated to be approximately 18 mg, 4) and geometric mean plasma individual isoflavonoid concentrations are 7 to 110 times higher in Japanese than in Finnish men. 5)Animal studies have shown that these two isoflavones inhibit carcinogen-induced tumors of mammary glands 6,7) and skin. 8) Recently, Onozawa et al. 9) reported that a soybean isoflavone mixture consisting of 74% genistein and 21% daidzein suppressed the development of invasive carcinomas of the rat prostate/seminal vesicles.In vitro studies have revealed that genistein is an inhibitor of protein tyrosine kinase, which modulates several cellular activities and plays an important role in cell proliferation and cell transformation, 10,11) and also inhibits mammalian DNA topoisomerase II 12) as well as angiogenesis. 13)Genistein and daidzein both have a heterocyclic phenol structure that closely resembles estrogens and enables them to bind to estrogen receptors and to exert weak estrogenic activities. 14-17) Normally soybeans and their products contain glycosides of the isoflavones, genistin and daidzin, and these are deglycosylated by intestinal β-glucuronidase to afford the active forms, genistein and daidzein. We have established an animal model of prostate cancer using 3,2′-dimethyl-4-aminobiphenyl (DMAB). 18,19) This carcinogen induces non-invasive prostate adenocarcinomas limited to the ventral lobe, but invasive and metastasizing adenocarcinomas originating from the d...

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Section: Discussionsupporting

confidence: 90%

Suppressive Effects of Dietary Genistin and Daidzin on Rat Prostate Carcinogenesis

Kato

Takahashi

Chen

et al. 2000

Japanese Journal of Cancer Research

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“…Ventral prostate carcinomas at week 60 all demonstrated strongly positive nuclei. 8) Evaluation of AR staining in atypical hyperplasias at weeks 46 or 60 in castrated groups was available only for the anterior prostate and seminal vesicles, castration not causing any change in staining intensity. While atypical hyperplasias of the anterior prostate and seminal vesicles were positive for AR immunostaining, invasive carcinomas of the anterior prostate or seminal vesicles developing in either castrated or non-castrated animals which had been treated with DMAB and TP were completely negative (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…9) In accordance with the androgen-dependent growth and function of all parts of the accessory sex organs, nontumorous epithelial cells were immunohistochemically found to be strongly positive for AR, as observed in a previous study. 8) It is important to note that all atypical hyperplasias examined were more or less positive. Our findings on the incidences of the lesions and AR immunostaining indicate that atypical hyperplasias and carcinomas of the ventral prostate and atypical hyperplasias, but The number of lesions was unfortunately very limited in groups undergoing orchiectomy, so that an in-depth analysis of AR status at weeks 41 and 60 was not possible.…”

Section: Discussionmentioning

confidence: 99%

“…AR immunohistochemistry was carried out by the methods described previously. 8) After deparaffinization, rehydration and heating in a microwave oven following washing with phosphate-buffered saline, the sections were treated with 2% goat serum at 4°C to block nonspecific binding, and then incubated overnight at 4°C with the polyclonal rabbit antibody PG21 12) at a concentration of 2.0 µg IgG/ml. Binding was visualized by the avidinbiotin-peroxidase complex method with 0.05% 3,3′-diaminobenzidine.…”

Section: Methodsmentioning

confidence: 99%

“…7) Our previous work with immunohistochemical analysis of androgen receptors showed most ventral prostate carcinomas to be positive while more than 80% of invasive carcinomas arising from the dorsolateral prostate and seminal vesicle proved negative. 8) Since normal glandular epithelial cells and atypical hyperplasias, regardless of the location in the accessory sex organs, are positive for androgen receptor (AR) immunohistochemistry, alteration in AR signalling might be a critical step for progression from atypical hyperplasias to invasive carcinomas. Orchiectomy after 20-week administration of testosterone to DMAB-treated animals resulted in development of a few cases of invasive carcinomas by the end of the experiment, suggesting that androgen-independent lesions can indeed be induced.…”

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Development of Androgen‐independent Carcinomas from Androgen‐dependent Preneoplastic Lesions in the Male Accessory Sex Organs of Rats Treated with 3,2′‐Dimethyl‐4‐aminobiphenyl and Testosterone Propionate

Iwasaki

Kato

Mori

et al. 1999

Japanese Journal of Cancer Research

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Two kinds of cancer can be induced in rat male accessory sex organs, one a non-invasive carcinoma arising in the ventral lobe and the other an invasive lesion which develops in the dorsolateral and anterior lobe as well as the seminal vesicles. In the present study, one group of male rats were given biweekly s.c. injections of 3,2′ ′ ′ ′-dimethyl-4-aminobiphenyl (DMAB) for 20 weeks for induction of non-invasive carcinomas and the other group received DMAB with 40-week testosterone propionate for induction of invasive carcinomas. Half of the animals in each group were then subjected to bilateral orchiectomy at week 41 to remove testicular androgen, in order to examine the androgen dependence of both types of carcinomas as well as precancerous lesions. Animals were killed at weeks 41, 46 and 60. All parts of the prostate complex showed involution and significant weight reduction after castration, with a complete disappearance of atypical hyperplasias and carcinomas of the ventral prostate. However, in spite of suppression of development of atypical hyperplasias in the anterior prostate and seminal vesicles, the incidence of invasive carcinomas was not changed. Normal epithelial cells and atypical hyperplasias of all parts of the prostate and seminal vesicles and carcinomas of the ventral prostate were immunohistochemically positive for nuclear androgen receptor, while invasive carcinomas that developed in either castrated or noncastrated animals were negative. These findings suggest that in the ventral prostate, both precancerous and cancerous lesions are androgen-dependent, but in the anterior and seminal vesicles, cancerous lesions (invasive carcinomas) are androgen-independent while precancerous lesions are hormone-dependent.Key words: Androgen-independent carcinoma -Rat -ProstateThe prostate glands require androgens for their growth, maintenance and function. Furthermore, development of tumors of the prostate is strongly related to the sex hormone status. For example, men castrated when young are reported not to develop prostate cancer.1) Deficiency of 5α-reductase, the enzyme which converts testosterone into the dihydrotestosterone active form in target organs is also linked to low susceptibility.2, 3) It is well known that prostate cancers are controllable by androgen deprivation therapy in early stages, but that androgen dependence is later lost, so lesions become incurable with hormone therapy.In experimental models, pharmacological doses of testosterone have been shown to increase development of naturally occurring or chemically-induced prostate carcinomas in rats. [4][5][6] We have reported that chronic administration of testosterone propionate (TP) at a pharmacological dose after 3,2′-dimethyl-4-aminobiphenyl (DMAB) induces invasive and partly metastatic adenocarcinomas, arising from the dorsolateral and anterior lobes, as well as the seminal vesicles. 7) Our previous work with immunohistochemical analysis of androgen receptors showed most ventral prostate carcinomas to be positive while more than 80% o...

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DNA methylation in the androgen receptor gene promoter region in rat prostate cancers

et al. 2002

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Immunohistochemically demonstrated androgen receptor expression in the rat prostate during carcinogenesis induced by 3,2′-dimethyl-4-aminobiphenyl with or without testosterone

Cited by 8 publications

References 13 publications

Suppressive Effects of Dietary Genistin and Daidzin on Rat Prostate Carcinogenesis

Suppressive Effects of Dietary Genistin and Daidzin on Rat Prostate Carcinogenesis

Development of Androgen‐independent Carcinomas from Androgen‐dependent Preneoplastic Lesions in the Male Accessory Sex Organs of Rats Treated with 3,2′‐Dimethyl‐4‐aminobiphenyl and Testosterone Propionate

DNA methylation in the androgen receptor gene promoter region in rat prostate cancers

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