The Androgen Derivative 5α-Androstane-3β,17β-Diol Inhibits Prostate Cancer Cell Migration Through Activation of the Estrogen Receptor β Subtype

Guerini, Vittoria; Sau, D.; Scaccianoce, Eugenia; Rusmini, P.; Ciana, Paolo; Maggi, Adriana; Martini, Paolo; Katzenellenbogen, Benita S.; Martini, L.; Motta, Marcella; Poletti, Angelo

doi:10.1158/0008-5472.can-04-1941

Cited by 127 publications

(111 citation statements)

References 52 publications

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“…In pursuit of a functional basis for this relationship, we demonstrated that ERβ sustains an epithelial phenotype and impedes a mesenchymal transition in prostate cancer and we identified a metabolite of dihydrotestosterone, 5α-androstane-3β,17β4-diol (3β-adiol) as the specific ERβ ligand that mediates this function (9). This observation is in agreement with the recent findings that 3β-adiol is a natural ligand for ERβ in prostate (13,(15)(16)(17).…”

supporting

confidence: 93%

“…The ligand dependency of ERβ-mediated regulation of PHD2 expression was evaluated by treating both PNT1a and LNCaP cells with 3β-adiol, a natural ligand for ERβ in the prostate (9,13,(15)(16)(17). Indeed, 3β-adiol treatment caused a significant increase in PHD2 mRNA and protein expression in both cell types Author contributions: P.M., C.C., and A.M.M.…”

Section: Phd2 Expression Is Regulated By Ligand-dependent Activation mentioning

confidence: 99%

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Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

Mak

Chang

Pursell

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Estrogen receptor β (ERβ) promotes the degradation of hypoxia inducible factor 1α (HIF-1α), which contributes to the ability of this hormone receptor to sustain the differentiation of epithelial and carcinoma cells. Although the loss of ERβ and consequent HIF-1 activation occur in prostate cancer with profound consequences, the mechanism by which ERβ promotes the degradation of HIF-1α is unknown. We report that ERβ regulates the ligand (3β-adiol)-dependent transcription of prolyl hydroxylase 2 (PHD2) also known as Egl nine homolog 1 (EGLN1), a 2-oxoglutarate-dependent dioxygenase that hydroxylates HIF-1α and targets it for recognition by the von Hippel-Lindau tumor suppressor and consequent degradation. ERβ promotes PHD2 transcription by interacting with a unique estrogen response element in the 5′ UTR of the PHD2 gene that functions as an enhancer. PHD2 itself is critical for maintaining epithelial differentiation. Loss of PHD2 expression or inhibition of its function results in dedifferentiation with characteristics of an epithelial-mesenchymal transition, and exogenous PHD2 expression in dedifferentiated cells can restore an epithelial phenotype. Moreover, expression of HIF-1α in cells that express PHD2 does not induce dedifferentiation but expression of HIF-1α containing mutations in the proline residues that are hydroxylated by PHD2 induces dedifferentiation. These data describe a unique mechanism for the regulation of HIF-1α stability that involves ERβ-mediated transcriptional regulation of PHD2 and they highlight an unexpected role for PHD2 in maintaining epithelial differentiation.T he role of estrogen receptors (ERs), which are transcription factors belonging to the steroid/thyroid nuclear receptor superfamily (1-3), in regulating epithelial differentiation is an emerging area of considerable biological interest and pathological relevance. In the prostate, the discovery of ERβ (4, 5) has generated intense interest in the roles played by this ER in several tissues including prostate and breast epithelia (6-11). Increasing evidence supports the hypothesis that ERβ functions to maintain epithelial differentiation in the prostate and breast (9,10,12,13). In the normal prostate, ERβ contributes to epithelial differentiation as evidenced by the observation that ERβ knockout mice exhibit altered differentiation in the ventral prostate, whereas the glands of ERα knockout mice lack these lesions and appear to be normal (12). ERβ in human prostate cancer is of substantial relevance because there is an inverse relationship between the expression of ERβ and highly invasive prostate cancer (9,14). In pursuit of a functional basis for this relationship, we demonstrated that ERβ sustains an epithelial phenotype and impedes a mesenchymal transition in prostate cancer and we identified a metabolite of dihydrotestosterone, 5α-androstane-3β,17β4-diol (3β-adiol) as the specific ERβ ligand that mediates this function (9). This observation is in agreement with the recent findings that 3β-adiol is a natural ligand for ERβ in ...

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supporting

confidence: 93%

Section: Phd2 Expression Is Regulated By Ligand-dependent Activation mentioning

confidence: 99%

Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

Mak

Chang

Pursell

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…41 It has also been shown that ERb negatively affects malignant cell tumorigenesis. 19,42,43 Although to our knowledge the exact correlation between ERb expression and tumor progression in thymic epithelial tumors is still unclear, ERb is suggested as a potential target in the treatment of ERb-positive thymomas and thymic carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Steroid receptor expression in thymomas and thymic carcinomas

Mimae

Tsuta

Takahashi

et al. 2011

Cancer

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BACKGROUND: Although protein expressions of glucocorticoid receptor (GR), estrogen receptors (ERa and ERb), progesterone receptor A (PgR-A), and androgen receptor (AR) were shown to play roles in the growth and differentiation of normal thymus and thymic tumors, to the authors' knowledge their association with patient characteristics and prognosis has yet to be determined. METHODS: A series of 140 thymic epithelial tumors (57 type A þ AB thymomas, 40 type B1 þ B2 thymomas, 6 type B3 thymomas, and 37 thymic carcinomas) were examined for GR, ERa, ERb, PgR-A, and AR expression using immunohistochemistry. In addition, the correlation between expression of these hormone receptors and clinicopathologic factors and overall survival (OS) was assessed. RESULTS: GR and ERb demonstrated a high rate of expression in thymomas and thymic carcinomas (82.9% and 76.4%, respectively), whereas rates of ERa, PgR-A, and AR expression were low (13.6%, 0.71%, and 23.6%, respectively). A significant correlation (P < .05) was found between ERa expression and tumor size and between ERb expression and tumor stage. Multivariate analyses revealed that histologic subtype (P ¼ .0039), tumor stage (P ¼ .0012), and GR expression (P ¼ .0025) were significantly correlated with the 10-year OS rate. CONCLUSIONS: GR and ERb demonstrated high rates of expression in thymomas and thymic carcinomas. Furthermore, multivariate analysis revealed that GR expression was associated with better prognosis in patients with surgically resected thymomas and thymic carcinomas. Cancer 2011;117:4396-

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“…It has been known for some time that 3βAdiol can bind to both ERα and ERβ with approximately 30-fold and 14-fold lower affinity relative to that of E2, respectively, suggesting slight specificity for ERβ [13]. 3βAdiol has been extensively characterized as an ERβ ligand in in vitro ERβ-promoter driven luciferase assays [18,19], gene expression assays [20,21], and in vivo prostate and prostate cancer models [22,23]. 3βAdiol has been shown to play a well defined role in prostate cancer etiology as an ERβ ligand.…”

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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The Androgen Derivative 5α-Androstane-3β,17β-Diol Inhibits Prostate Cancer Cell Migration Through Activation of the Estrogen Receptor β Subtype

Cited by 127 publications

References 52 publications

Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

Steroid receptor expression in thymomas and thymic carcinomas

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

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