Autoregulation of Estrogen and Androgen Receptor mRNAs and Downregulation of Androgen Receptor mRNA by Estrogen in Primary Cultures of Lizard Testis Cells

Cardone, A; Angelini, F.; Varriale, Bruno

doi:10.1006/gcen.1998.7063

Cited by 57 publications

(30 citation statements)

References 35 publications

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“…Reducing AR levels by these various means results in the inhibition of prostate cancer cell growth and PSA expression, while the small interfering RNA knockdown of AR expression also leads to significant apoptotic cell death in androgen-sensitive and AIPC cells (39 -41). Various studies have shown that estrogens have the ability to down-regulate AR expression in different target cells (12,14,42). In particular, studies from our laboratory have shown that MCF-7 breast cancer cells treated with E 2 exhibited significantly lower levels of AR (12).…”

Section: Discussionmentioning

confidence: 88%

Fulvestrant (ICI 182,780) down-regulates androgen receptor expression and diminishes androgenic responses in LNCaP human prostate cancer cells

Bhattacharyya

Krishnan

Swami

et al. 2006

Molecular Cancer Therapeutics

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The androgen receptor (AR) plays a key role in the development and progression of prostate cancer. Targeting the AR for down-regulation would be a useful strategy for treating prostate cancer, especially hormone-refractory or androgen-independent prostate cancer. In the present study, we showed that the antiestrogen fulvestrant [ICI 182,780 (ICI)] effectively suppressed AR expression in several human prostate cancer cells, including androgenindependent cells. In LNCaP cells, ICI (10 Mmol/L) treatment decreased AR mRNA expression by 43% after 24 hours and AR protein expression by f50% after 48 hours. We further examined the mechanism of AR downregulation by ICI in LNCaP cells. ICI did not bind to the T877A-mutant AR present in the LNCaP cells nor did it promote proteasomal degradation of the AR. ICI did not affect AR mRNA or protein half-life. However, ICI decreased the activity of an AR promoter-luciferase reporter plasmid transfected into LNCaP cells, suggesting a direct repression of AR gene transcription. As a result of AR down-regulation by ICI, androgen induction of prostate-specific antigen mRNA and protein expression were substantially attenuated. Importantly, LNCaP cell proliferation was significantly inhibited by ICI treatment. Following 6 days of ICI treatment, a 70% growth inhibition was seen in androgen-stimulated LNCaP cells. These data show that the antiestrogen ICI is a potent AR downregulator that causes significant inhibition of prostate cancer cell growth. Our study suggests that AR downregulation by ICI would be an effective strategy for the treatment of all prostate cancer, especially AR-dependent androgen-independent prostate cancer. [Mol Cancer Ther 2006;5(6):1539 -49]

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Section: Discussionmentioning

confidence: 88%

Fulvestrant (ICI 182,780) down-regulates androgen receptor expression and diminishes androgenic responses in LNCaP human prostate cancer cells

Bhattacharyya

Krishnan

Swami

et al. 2006

Molecular Cancer Therapeutics

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“…The uterine regulation of SFRP-2 is an interesting observation, since very few genes are known to be down-regulated by estrogen (61)(62)(63)(64)(65). To our knowledge, this is a gene that is abundantly expressed in quiescent uterine stromal cells but is down-regulated by estrogens.…”

Section: Fig 8 Effects Of P 4 On Estrogen-induced Uterine Expressiomentioning

confidence: 97%

Estrogen Targets Genes Involved in Protein Processing, Calcium Homeostasis, and Wnt Signaling in the Mouse Uterus Independent of Estrogen Receptor-α and -β

Das¹,

Tan²,

Raja³

et al. 2000

Journal of Biological Chemistry

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Estrogen actions in target organs are normally mediated via activation of nuclear estrogen receptors (ERs). By using mRNA differential display technique, we show, herein, that estradiol-17␤ (E 2 ) and its catechol metabolite 4-hydroxy-E 2 (4OHE 2 ) can modulate uterine gene expression in ER␣(؊/؊) mice. Whereas administration of E 2 or 4OHE 2 rapidly up-regulated (4 -8-fold) the expression of immunoglobulin heavy chain binding protein (Bip), calpactin I (CalP), calmodulin (CalM), and Sik similar protein (Sik-SP) genes in ovariectomized wildtype or ER␣(؊/؊) mice, the expression of secreted frizzled related protein-2 (SFRP-2) gene was down-regulated (4-fold). Bip, CalP, and CalM are calcium-binding proteins and implicated in calcium homeostasis, whereas SFRP-2 is a negative regulator of Wnt signaling. Bip and Sik-SP also possess chaperone-like functions. Administration of ICI-182,780 or cycloheximide failed to influence these estrogenic responses, demonstrating that these effects occur independent of ER␣, ER␤, or protein synthesis. In situ hybridization showed differential cell-specific expression of these genes in wild-type and ER␣(؊/؊) uteri. Although progesterone can antagonize or synergize estrogen actions, it had minimal effects on these estrogenic responses. Collectively, the results demonstrate that estrogens have a unique ability to influence specific genes in the uterus not involving classical nuclear ERs.Estrogens regulate diverse physiological responses including normal functioning of the reproductive and cardiovascular systems and bone metabolism (1-3). The uterus is a primary target for various estrogenic responses during the cycle and pregnancy. In the mouse, estrogen induces uterine epithelial cell proliferation, and together with progesterone (P 4 ) 1 it directs stromal cell proliferation and epithelial cell differentiation. These coordinated estrogen and P 4 interactions prepare the uterus to the receptive state for implantation (reviewed in Ref. 4). The mechanism by which estrogen renders the P 4 -primed uterus receptive for implantation is not clearly understood.Estrogen actions are primarily executed by its binding to nuclear estrogen receptors, ER␣ and/or ER␤, which are ligandinducible transcription factors (5, 6). They modulate transcription of genes by virtue of their binding as hormone receptor complexes to specific DNA sequences (hormone response elements) in target promoters (5, 6). Despite the classical estrogenic actions, there is increasing evidence that gene transactivation or modulation of cell functions by estrogens is also mediated independent of nuclear ERs (7-10). In many cells, a myriad of estrogenic effects occurs rapidly within seconds or minutes. These responses do not require RNA or protein synthesis and are considered to be mediated by estrogen binding to the plasma membrane (10 -12). For example, increases in intracellular cAMP, calcium influx, inositol triphosphate, and release of prolactin are all attributed to membrane-mediated estrogen actions (10 -12). Although the pre...

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“…Using testicular cell cultures, Cardone et al (1998) showed that both estrogen and androgen may autoregulate the expression of their own receptor mRNAs, yet estrogen can downregulate AR mRNA.…”

Section: Introductionmentioning

confidence: 99%

Effects of maternal undernutrition during lactation on aromatase, estrogen, and androgen receptors expression in rat testis at weaning

Teixeira¹,

Silandre²,

Santos³

et al. 2007

Journal of Endocrinology

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The goal of this study was to evaluate the effects of maternal malnutrition during lactation on serum levels of testosterone and estradiol, testicular testosterone concentration, aromatase, testicular androgen (AR) and estrogen a (ERa) receptors expression in the pups at weaning. From parturition until weaning, Wistar rats were separated into three groups: (C) control group, with free access to a standard laboratory diet containing 23% protein; protein-energy restricted (PER) group, with free access to an isoenergy and protein-restricted diet containing 8% protein; and energy-restricted (ER) group, receiving standard laboratory diet in restricted quantities, which were calculated according to the mean ingestion of the PER group. All pups were killed at weaning, corresponding to 21 days post partum. Compared with the C group, body weights (CZ48G2 . 3 g; PERZ20G1 . 3 g; ERZ25 . 4G0 . 9 g; P!0 . 01) and testicular weights (CZ0 . 15G0 . 02 g, PERZ0 . 05G0 . 01 g, ERZ0 . 06G 0 . 02 g, P!0 . 001) of both PER and ER groups were lower.However, there was no significant difference in the testicular/body weight ratio in PER and ER groups compared with the C group. The testosterone serum concentration (ng/ml) was significantly higher in the PER group compared with ER and C groups (CZ0 . 09G0 . 012; PERZ0 . 45G0 . 04; ERZ0 . 15G0 . 03, P!0 . 01). Testicular testosterone concentration (CZ2 . 1G0 . 43; PERZ6 . 5G0 . 7; ERZ13G2 . 3, P!0 . 01) was increased in treated groups when compared with controls. The estradiol serum concentration (pg/ml) was lower in both dietary groups (CZ74G 4 . 6; PERZ49G3 . 2; ERZ60G5 . 5, P!0 . 01). The amounts of aromatase mRNA and ERa transcripts were significantly lower (P!0 . 05) in PER and ER groups; conversely AR (both mRNA and protein) was significantly enhanced (P!0 . 05) in treated animals. The nutritional state in early phases of development is important since we have demonstrated here that the maternal malnutrition during lactation leads to alterations in estradiol and testosterone serum concentrations, testicular testosterone concentration, AR and ERa expression together with a decrease of aromatase expression. All together, these changes of steroid status may be deleterious for future germ cell development and reproductive function of these male pups submitted to early malnutrition.

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Autoregulation of Estrogen and Androgen Receptor mRNAs and Downregulation of Androgen Receptor mRNA by Estrogen in Primary Cultures of Lizard Testis Cells

Cited by 57 publications

References 35 publications

Fulvestrant (ICI 182,780) down-regulates androgen receptor expression and diminishes androgenic responses in LNCaP human prostate cancer cells

Fulvestrant (ICI 182,780) down-regulates androgen receptor expression and diminishes androgenic responses in LNCaP human prostate cancer cells

Estrogen Targets Genes Involved in Protein Processing, Calcium Homeostasis, and Wnt Signaling in the Mouse Uterus Independent of Estrogen Receptor-α and -β

Effects of maternal undernutrition during lactation on aromatase, estrogen, and androgen receptors expression in rat testis at weaning

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