Comparisons of the effects of tamoxifen, toremifene and raloxifene on enzyme induction and gene expression in the ovariectomised rat uterus

Abstract

This study compares the actions of oestradiol, tamoxifen, toremifene and raloxifene on enzyme and gene expression in uterine tissues of ovariectomised rats over 72 h. The time-course for the induction of ornithine decarboxylase by the compounds showed a rapid biphasic response, while for creatine kinase brain type (BB) there was a continued increase over 72 h. The efficacy of induction showed that, with both markers, oestradiol gave the highest induction level, followed by tamoxifen or toremifene and then raloxifene. RT-PCR demonstrated that all compounds decreased oestrogen receptor (ER) , ER and ER 2 gene expression, 8-24 h after the first dose, suggesting that down-regulation of ER is not the primary cause of the difference in efficacy between these compounds. Using cDNA arrays, expression of 512 genes was examined in the uteri of oestradiol-or tamoxifen-treated rats. Both compounds resulted in the up-regulation of heat-shock protein 27, telomerase-associated protein 1 and secretin. However, most surprising was the marked downregulation of Wilms' tumour and retinoblastoma genes. We speculate that this may result in a loss of regulation of the transition from the G1 to the S phase in the cell cycle and may make cells more vulnerable to the carcinogenic effects of tamoxifen in this tissue.

Identification of temporal patterns of gene expression in the uteri of immature, ovariectomized mice following exposure to ethynylestradiol

“…Numerous responses were observed that agree well with published data, as described in the DISCUSSION. However, there were also several well-established estrogen-regulated responses not observed in this study, including Cdk5 (p1z ϭ 0.130) (3), Ccnd3 (p1z ϭ 0.997) (3,25), estrogen-responsive finger protein (Trim25; p1z ϭ 0.999) (50), Rb1 (p1z ϭ 0.559) (27), and syndecan 3 (Sdc3; p1z ϭ 0.248) (63). In several cases, they were associated with low p1z values or lacked a significant treatment-by-time interaction ANOVA term, and in some cases these were considered absent by the MAS5 software.…”

Gene Expression Is Differentially Regulated in the Epididymis after Orchidectomy

“…Similarly, gene expression analysis can provide insight into the physiological processes regulated by hormones in their target organs. Complementary DNA (cD NA) microarray technology has been used to investigate estrogen action in breast cancer cells and in the uterus [265,266], thyroid hormone action in the liver [267], and androgen action in normal and pathological conditions in the prostate [268].…”

Comparative effects of estradiol, methyl-piperidino-pyrazole, raloxifene, and ICI 182 780 on gene expression in the murine uterus

“…2007). Only a few studies to date have examined in detail the global gene expression changes in the uteri of mice or rats in response to an ESR-specific SERM (Green et al . 2001, Hewitt et al .…”