Estrogen receptor-beta agonist diarylpropionitrile counteracts the estrogenic activity of estrogen receptor-alpha agonist propylpyrazole-triol in the mammary gland of ovariectomized Sprague Dawley rats

Song, Xiaoyu; Pan, Zhong-Zong

doi:10.1016/j.jsbmb.2011.12.018

Cited by 19 publications

(15 citation statements)

References 72 publications

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“…Interestingly, oral retinoid treatment has been shown to be less effective in female PC patients relative to males (Gruber et al, 2012). Further, our results significantly extend the case in support of K16 (Kerns et al, 2016) and estrogen receptor β (Song and Pan, 2012) as positive regulators of NRF2 function and the associated redox balance in skin keratinocytes.…”

Section: Resultssupporting

confidence: 80%

“…Since ER-β reportedly exerts a positive impact on NRF2 signaling, we performed topical treatments of SF in combination with pre-treatment intra-peritoneal injections of diarylpropionitrile (DPN), an ER-β selective agonist that has been shown to also oppose ER-α activity (Song and Pan, 2012). Compared with vehicle-treated controls, Krt16 -/- females treated with the dual treatment regimen showed a remarkable reduction in PPK lesion development (Figure 4A), with a significant decrease in PPK index from 33.7 ± 4.0 for SF + PBS treated to 0.5 ± 0.1 for SF + DPN treated Krt16 -/- female mice (mean ± SEM; Student's t test, P value < 0.005; Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

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Sexual Dimorphism in Response to an NRF2 Inducer in a Model for Pachyonychia Congenita

Kerns

Hakim

Zieman

et al. 2018

Journal of Investigative Dermatology

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Sex is an influential factor regarding pathophysiology and therapeutic response in human disease. Pachyonychia congenita (PC) is caused by mutations in keratin genes and typified by dystrophic lesions affecting nails, glands, oral mucosa, and palmar-plantar epidermis. Painful palmar-plantar keratoderma (PPK) severely impair mobility in PC. Mice genetically null for keratin 16 (Krt16), one of the genes mutated in PC, develop PC-like PPK. In male Krt16-/- mice, oxidative stress associated with impaired glutathione synthesis and NRF2-dependent gene expression precedes PPK onset, which can be prevented by topical sulforaphane (SF)-mediated activation of NRF2 (Kerns et al., J. Clin. Invest. 126:2356-66). We report here that SF treatment fails to activate NRF2 and prevent PPK in female Krt16-/- mice despite a similar set of molecular circumstances. Follow-up studies reveal a temporal shift in PPK onset in Krt16-/- females, coinciding with sex-specific fluctuations in footpad skin glutathione levels. Dual treatment with SF and diarylproprionitrile (DPN), an estrogen receptor beta (ER-β) selective agonist, results in NRF2 activation, normalization of glutathione levels, and prevention of PPK in female Krt16-/- mice. These findings point to a sex difference in NRF2 responsiveness that needs be considered when exploring NRF2 as a therapeutic target in skin disorders.

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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Sexual Dimorphism in Response to an NRF2 Inducer in a Model for Pachyonychia Congenita

Kerns

Hakim

Zieman

et al. 2018

Journal of Investigative Dermatology

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“…We hypothesize that these examples reflect the actions of estradiol through ERβ. While our findings from the current study do not directly support the hypothesis that ERβ activation promotes prosocial behavior, our negative findings in E2-treated voles might suggest that ERβ activation can counteract the negative effects of ERα activation on prosocial behavior and aggression- consistent with numerous other studies demonstrating an antagonistic relationship between ERα and ERβ (Mazzucco et al, 2008; SÃ et al, 2013; Song and Pan, 2012). However, future studies will need to directly address this possibility by treating subjects with combinations of PPT and DPN, or with E2 in conjunction with selective antagonists (Santollo et al, 2010).…”

Section: Discussionsupporting

confidence: 69%

Effects of postnatal estrogen manipulations on juvenile alloparental behavior

Perry

Carter

Cushing

2015

Hormones and Behavior

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Sex- and species-specific patterns of estrogen receptor (ER)-α expression are established early in development, which may contribute to sexual differentiation of behavior and determine male social organization. The current study investigated the effects of ERα and ERβ activation during the second postnatal week on subsequent alloparental behavior and ERα expression in juvenile prairie voles. Male and female pups were treated daily with 17β-estradiol (E2, ERα/ERβ agonist), PPT (selective ERα agonist), DPN (selective ERβ agonist), or the oil vehicle on postnatal days (PD) 8-14. Alloparental behavior and ERα expression were examined at PD21. PPT treatment inhibited prosocial motivation in males and increased pup-directed aggression in both sexes. E2 and DPN had no apparent effect on behavior in either sex. PPT-treated males had increased ERα expression in the medial preoptic area (MPN), medial amygdala (MEApd) and bed nucleus of the stria terminalis (BSTpr). DPN treatment also increased ERα expression in males, but only in the BSTpr. Female ERα expression was unaffected by treatment. These results support the hypothesis that ERα activation in early life is associated with less prosocial patterns of central ERα expression and alloparental behavior in males. The lack of an effect of E2 on behavior suggests that ERβ may antagonize the effects of ERα on alloparental behavior. The results in DPN-treated males suggest that ERα in the MEApd, and not the BSTpr, may be a primary determinant of alloparental behavior in males.

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“…ER beta over-expression inhibits tumor establishment and growth as well as E2-induced tumor formation “in vivo” in mouse xenografts of ER alpha-positive MCF-7 and T47D breast cancer cells (Paruthiyil S et al ., 2004; Behrens D et al, 2007; Hartman J et al ., 2006) Indeed, ER beta induces inhibition of classical estrogen-regulated genes, such as VEGF and PDGFβ (Hartman J et al, 2006). Recently, Song and Pan (Song K and Pan ZZ, 2012) demonstrated that ER alpha-mediated estrogenic activity in the mammary gland can be opposed by the ER beta and selective agonists such as DPN may be explored for the development of better hormone replacement therapy (HRT) regimens to reduce or eradicate the risk for breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor beta binds Sp1 and recruits a corepressor complex to the estrogen receptor alpha gene promoter

Bartella

Rizza

Barone

et al. 2012

Breast Cancer Res Treat

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Human estrogen receptors (ERs) alpha and beta are crucially involved in the regulation of mammary growth and development. Normal breast tissues display a prevalently expression of ER beta than ER alpha, which drastically increases during breast tumorogenesis. So, it is reasonable to assume how a dysregulation of the two estrogen receptor subtypes may induce breast cancer development. However, the molecular mechanism underlying the opposite role played by the two estrogen receptors on tumor cell growth remains to be elucidated. In the present study, we have demonstrated that ER beta overexpression in breast cancer cells decreases cell proliferation and down-regulates ER alpha mRNA and protein content along with a concomitant repression of estrogen-regulated genes. Transient transfection experiments, using a vector containing the human ER alpha promoter region, showed that elevated levels of the ER beta down-regulated basal ER alpha promoter activity. Furthermore, side-directed mutagenesis and deletion analysis have revealed that the proximal GC-rich motifs at −223 and −214 is crucial for the ER beta-induced ER alpha down-regulation in breast cancer cells. This occurred through ER beta-Sp1 protein-protein interaction within the ER alpha promoter region and the recruitment of a corepressor complex containing NCoR/SMRT (nuclear receptor corepressor/silencing mediator of retinoic acid and thyroid hormone receptor), accompanied by hypoacetylation of histone H4 and displacement of RNA polymerase II. Silencing of NCoR gene expression by RNA interference reversed the down-regulatory effect of ER beta on ER alpha gene expression and cell proliferation. Our results provide evidence for a novel mechanism by which overexpression of ER beta through NCoR is able to down regulate ER alpha gene expression, thus inhibiting ER alpha’s driving role on breast cancer cell growth.

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Estrogen receptor-beta agonist diarylpropionitrile counteracts the estrogenic activity of estrogen receptor-alpha agonist propylpyrazole-triol in the mammary gland of ovariectomized Sprague Dawley rats

Cited by 19 publications

References 72 publications

Sexual Dimorphism in Response to an NRF2 Inducer in a Model for Pachyonychia Congenita

Sexual Dimorphism in Response to an NRF2 Inducer in a Model for Pachyonychia Congenita

Effects of postnatal estrogen manipulations on juvenile alloparental behavior

Estrogen receptor beta binds Sp1 and recruits a corepressor complex to the estrogen receptor alpha gene promoter

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