Estrogen enhancement of androgen‐responsive gene expression in hormone‐induced hyperplasia in the ventral prostate of F344 rats

Abstract

It has been postulated that, in addition to the crucial role of androgens, estrogens may be involved in development of prostate hyperplasia and cancer. In rats, combined administration of estrogen and androgen synergistically increases ventral prostate weight, and continued treatment results in the development of glandular hyperplasia. Prostate adenocarcinoma can be induced by chemical carcinogens in rats, and estrogen given together with an androgen generally shortens the latent period or increases the incidence and/or multiplicity of carcinomas. However, the mechanisms responsible for these synergistic effects of estrogen and androgen are poorly understood. In the present study, we examined the combined effects of 17β β β β-estradiol (E2) and testosterone (T) on gene expression in an early stage of prostate hyperplasia in an F344 rat model. ERα α α α expression, which has been suggested to contribute to development of prostatic hyperplasia, was increased by the combined treatment with T and E2, while it was suppressed by T alone. Expression levels of two androgen-responsive genes, probasin and kallikrein S3, were increased in the ventral prostate of rats treated with T plus E2 for 4 weeks in a dose-dependent manner, while short-term treatment did not alter the expression. These results suggested that enhancing effects of E2 on transcription of androgen-responsive genes, as well as an increased level of ERα α α α may play roles in the synergistic effects of E2 on T-induced prostate hyperplasia. ndrogen plays a crucial role in development of benign prostatic hyperplasia (BPH) and prostate cancer (PC), but it has been postulated that estrogens may also be involved. In humans, BPH is known to be linked with both serum estrogen levels and urinary estrogen content.1, 2) Canine BPH is inducible by simultaneous administration of androstanediol and estradiol, 3) and in rats, administration of estrogen concomitantly with androgen promotes prostate growth. 4) Furthermore, combined estrogen and androgen treatment enhances prostate carcinogenesis in Noble rats and in chemical carcinogen-treated F344 rats.5, 6) Radioligand-binding assays and immunohistochemical studies with ERα antibodies have demonstrated the presence of ER in both BPH and prostate carcinomas, but with no apparent correlation between receptor levels and pathologic features.7) The discovery of ERβ has given rise to a new understanding of the physiological roles of ER. 8,9) In ERβ knockout mice, multiple hyperplastic foci are observed in the ventral prostate 10) and immunohistochemical studies in human prostate cancer have provided evidence of decreased ERβ expression in human BPH and PC. 11,12) These findings suggest that estrogen receptors are involved in regulating cell proliferation and in carcinogenesis in the prostate gland.In the present study, we examined the combined effects of 17β-estradiol (E2) and testosterone (T) on gene expression in an early stage of prostate hyperplasia in an F344 rat model. RNAs isolated from the ventral prostate tissue wer...

Androgen dependent transcription of a mouse prostatic protein gene, PSP94: Involvement of estrogen receptors

“…In the previous study, we examined the expression of prostatic protein genes such as probasin and kallikrein S3 to understand the molecular mechanism underling the androgen plus estrogen effect [29]. We found that estradiol enhanced the androgen dependent expression of prostatic genes along with increase in ER␣ expression, which suggested that the elevated prostatic ER␣ may contribute to the enhancing effects.…”

Both nongenomic and genomic effects are involved in estradiol's enhancing the phenotype of smooth muscle cells in cultured prostate stromal cells

“…The ratio of estrogen to androgen increases both in the serum and in the prostate gland along with aging of men [4,5], which has a strong correlation with the process of prostate hyperplasia. Many research data have demonstrated that estrogens can regulate the proliferation and differentiation of prostate stromal and epithelial cells [6][7][8][9][10][11][12][13][14][15].…”

Interactions between Dietary Factors and Inflammation in Prostate Carcinogenesis

“…Fujimoto et al showed that estrogen receptor a mRNA is expressed in the rat ventral prostate (41), and that estrogen and testosterone together up-regulated the expression of estrogen receptor a mRNA (41). In addition, estrogen, along with testosterone, resulted in increased expression of androgenresponsive genes (41). Estrogens can induce prostate inflammation in the rat and have been postulated to play a role in increasing the risk for human prostate cancer (42).…”