Early onset of puberty and early ovarian failure in CYP7B1 knockout mice

Omoto, Yoko; Lathe, Richard; Warner, Margaret; Gustafsson, Jan Åke

doi:10.1073/pnas.0500198102

Cited by 47 publications

(33 citation statements)

References 28 publications

(30 reference statements)

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“…Reporter studies have suggested that androgen metabolites (largely undefined in these studies) can induce the expression of an estrogen-responsive luciferase construct, but little further analysis of the function of these metabolites has been reported [11,27]. Interestingly, female knockout mice generated by Omoto et al that lack expression of CYP7B1 (the enzyme responsible for the elimination of 3βAdiol ) showed increased proliferation of both mammary and other reproductive tissues, as well as early onset of puberty and early ovarian failure, suggesting that 3βAdiol is indeed estrogenic in the breast and reproductive tissues [28].…”

Section: Discussionmentioning

confidence: 99%

The androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance

Sikora

Cordero

Larios

et al. 2008

Breast Cancer Res Treat

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The aromatase inhibitors (AIs) are used to treat estrogen receptor-positive (ER+) breast tumors in post-menopausal women, and function by blocking the conversion of adrenal androgens to estrogens by the enzyme CYP19 aromatase. Breast cancer patients receiving AI therapy have circulating estrogen levels below the level of detection; however, androgen concentrations remain unchanged. We were interested in studying the effects of androgens on breast cancer cell proliferation under profound estrogen-deprived conditions. Using in vitro models of estrogen-dependent breast cancer cell growth we show that the androgens testosterone and 5α-dihydrotestosterone induce the growth of MCF-7, T47D and BT-474 cells in the absence of estrogen. Furthermore, we demonstrate that under profound estrogen-deprived conditions these breast cancer cells up-regulate steroidogenic enzymes that can metabolize androgens to estrogens. Lastly, we found that the downstream metabolite of 5α-dihydrotestosterone, 5α-androstane-3β,17β-diol (3βAdiol), is estrogenic in breast cancer cells, and induces growth and ER-signaling via activation of ERα. In conclusion, our results show that breast cancer cells deprived of estrogen up-regulate steroidogenic enzymes and metabolize androgens to estrogen-like steroids. The generation of estrogen-like steroids represents a potential mechanism of resistance to aromatase inhibitors.

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Section: Discussionmentioning

confidence: 99%

The androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance

Sikora

Cordero

Larios

et al. 2008

Breast Cancer Res Treat

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“…33 In our recent studies, we have shown that 3bAdiol is a strong binder of ERb1 41 and that CYP7B1 is the enzyme that regulates ERb1 function by regulating the level of 3bAdiol. 51,52 The brain phenotype of the CYP7B1 À/À mouse indicates that 3bAdiol is functional in the developing brain. There are at least two functions of 3bAdiol, one with regard to normal neuronal selection by apoptosis and the other one being participation in the control of ER expression.…”

Section: Dynamics Of Estrogen Receptors In the Brain N Sugiyama Et Almentioning

confidence: 99%

Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain

Sugiyama

Andersson

Lathe³

et al. 2008

Mol Psychiatry

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This study reports on the spatiotemporal dynamics of the expression of estrogen receptors (ERs) in the mouse central nervous system (CNS) during the early postnatal and the peripubertal period. At postnatal day 7 (P7), neurons with strong nuclear immunostaining for both ERa and ERb1 were widely distributed throughout the brain. Sucrose density gradient sedimentation followed by western blotting supported the histochemical evidence for high levels of both ERs at P7. Over the following 2 days, there was a rapid downregulation of ERs. At P9, ERa expression was visible only in the hypothalamic area. Decline in ERb1 expression was slower than that of ERa, and ERa-negative, ERb1-positive cells were observed in the dentate gyrus and walls of third ventricle. Between P14 and P35, ERs were undetectable except for the hypothalamic area. As before P7, the ovary does not produce estrogen but does produce 5a-androstane-3b, 17b-diol (3bAdiol), an estrogenic metabolite of dihydrotestosterone, we examined the effects of high levels of 3bAdiol in the postnatal period. We used CYP7B1 knockout mice which cannot hydroxylate and inactivate 3bAdiol. The brains of these mice are abnormally large with reduced apoptosis. In the early postnatal period, there was 1-week delay in the timing of the reduction in ER expression in the brain. These data reveal that the time when ERs might be activated in the brain is limited to the first 8 postnatal days. In addition, the importance of aromatase has to be reconsidered as the alternative estrogen, 3bAdiol, is important in neuronal function in the postnatal brain.

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“…However, the non-aromatizable androgenic hormone DHT can also be metabolized by 3β-hydroxysteroid dehydrogenase to 3βAdiol which has been shown to bind, although with a much lower affinity than E2, both ERα and ERβ [67]. During profound estrogen deprivation, 3βAdiol has been demonstrated to be estrogenic in the breast and reproductive tissues [68]. Indeed, 3βAdiol can induce the proliferation of breast cancer cells through direct activation of ERα [69].…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal Expression Pattern of Gadd45g Signaling Pathway Components in the Mouse Uterus Following Hormonal Steroid Treatments

2012

Endocrinol Metab Synd

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The uterus is a hormone-dependent organ under the control of estrogens, progestins and androgens. The actions of estradiol (E2) and progesterone on uterine physiology are well documented, while active androgens such as testosterone and dihydrotestosterone (DHT) are now also recognized to exert an important role to appropriately maintain the cyclical changes of the endometrium.Based on our previous observations that DHT modulates GADD45g and the expression of specific cell cycle genes, the aim of this study was to identify the specific uterine cell types in which these cell cycle genes are modulated by hormonal steroids.Using in situ hybridization and quantitative RT-PCR (QRT-PCR), the localization and measurement of mRNA expression of key cell cycle genes responding to E2 and DHT were performed in the uterus of ovariectomized mice. Interestingly, in situ hybridization experiments demonstrate that Gadd45g mRNA is detected early and strongly in stromal cells only, indicating that the early cell cycle arrest induced by DHT and E2 in the mouse uterus occurs in this compartment. On the other hand, the cell cycle stimulation represented by the late increase of Ccnb1, Cdc2a and Cdc25c gene expression is located exclusively in the glandular and luminal epithelial cells. QRT-PCR experiments confirm the regulation of mRNA expression observed following in situ hybridization. Surprisingly, both hormones appear to trigger effects in the same direction on cell cycle progression, with androgens inducing a lower modulation of gene expression levels. Additional experiments using the human uterine Ishikawa cell line confirmed the implication of the estrogen receptor in the GADD45g up-regulation following treatment with E2 while the regulation triggered by DHT is less clear. These observations illustrate clearly the stroma-epithelium interactions, which finely regulate the uterine physiology via paracrine mechanisms. Additional investigations are definitely needed to determine the exact role played by androgens in mouse uterine growth and differentiation.

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Early onset of puberty and early ovarian failure in CYP7B1 knockout mice

Cited by 47 publications

References 28 publications

The androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance

The androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance

Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain

Spatiotemporal Expression Pattern of Gadd45g Signaling Pathway Components in the Mouse Uterus Following Hormonal Steroid Treatments

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