The anti‐oestrogen fulvestrant (ICI 182,780) reduces the androgen receptor expression, ERK1/2 phosphorylation and cell proliferation in the rat ventral prostate

Abstract

This study proposed to investigate further the role of oestrogens during pubertal growth of rat ventral prostate, by analysing the effect of anti-oestrogen fulvestrant (ICI 182,780) on the expression of androgen (AR) and oestrogen receptors (ESR1 and ESR2), mitogen-activated protein kinase (ERK1/2) phosphorylation, and expression of Ki-67, a biomarker for cell proliferation. Ventral prostates were obtained from 90-day-old rats treated once a week for 2 months with vehicle (control) or ICI 182,780 (10 mg/rat, s.c.). Transcripts for AR, ESR1 and ESR2 were evaluated by quantitative real-time polymerase chain reaction. Expression of AR, ESR1, ESR2, total and phospho-ERK1/2 was analysed by Western blot or immunofluorescence. Ki-67-positive cells and myosin heavy chain were detected by immunohistochemistry. Cylindrical epithelial cells slightly taller, epithelial dysplasia and an increase in smooth muscle layer were observed in the ventral prostate from ICI 182,780-treated rats. ICI 182,780 did not change the mRNA, but decreased the protein levels for AR in the ventral prostate. The expression of ESR1 (mRNA and protein) was upregulated by ICI 182,780, but no changes were observed on ESR2 expression (mRNA and protein). ICI 182,780 decreased the phosphorylation state of ERK1/2, with no changes in total ERK1/2 levels. Ki-67-positive cells in the ventral prostate were also decreased by ICI 182,780. In conclusion, ICI 182,780 induces downregulation of AR expression and may block the translocation of ESR1 and ESR2 from the nucleus to the plasma membrane, decreasing ERK1/2 phosphorylation and prostatic epithelial cell proliferation. These findings provide a basis for physiological roles of oestrogen in the ventral prostate. Further studies with fulvestrant are necessary in benign prostate hyperplasia and prostatic cancer models.

Hsa-miRNA-765 as a Key Mediator for Inhibiting Growth, Migration and Invasion in Fulvestrant-Treated Prostate Cancer

“…Immunostaining was negligible in fulvestrant-treated specimens in almost all cancer foci (Figure 6C, p <0.01, n = 5). Androgen receptor was previously shown to be downregulated by fulvestrant in a rodent [41] and a cell model [21]. Here, we showed AR was also significantly downregulated in our clinical study (Figure 6B and C).…”

“…Mouse IgG and RNA polymerase II serve as negative and positive control, respectively. Fulvestrant induced 17 fold increase in ERβ recruitment when compared with non-ERβ binding region (the 0N promoter of ERβ [33], [41]). Student's t-test was performed to determine significance of between groups using a cutoff p value of 0.05.…”

“…This finding is consistent with several reports on the anti-PCa action of ERβ, such as inhibition of epithelial-mesenchymal transition [55], downregulation of VEGF-A [55] and TMPRSS2-ERG [56], reduction of PC3 cell migration and invasion in vitro [39], and growth of DU145 and PC3 xenografts in nude mice [20]. Other proposed mechanisms of action of fulvestrant include cross-talk of ERβ with the NFκB [19] or the KLF5 [20] signaling pathways to mediate cell death or anoikis, respectively, as well as suppression of androgen-receptor expression [21], [41] and its action [21].…”

Androgen Receptors, Sex Behavior, and Aggression

“…The implication is that oestrogen acts via the oestrogen receptor (ER). Further, studies have shown that oestrogens, possibly through the ER, can up-regulate AR expression both centrally (hypothalamus and amygdala) and peripherally (prostate) (98, 99). The most powerful evidence for a role of ER in mediating male sexual behaviour comes from ER knockout mice (100–102).…”

Seasonal variation in estrogen receptor ERα, but not ERβ, androgen receptor and aromatase, in the efferent ductules and epididymis of the big fruit-eating bat Artibeus lituratus

“…A constitutive expression of ERb in the efferent ductules of rats was previously described [36]. Unaltered ERb expression in other male genital organs submitted to different experimental designs has also been found [2,3,11,15,40,42,48]. During the annual reproductive cycle of hibernating bats, there is a drastic change in testosterone, but not dihydrotestosterone (DHT), and androstenedione levels [26].…”