Prostate phenotypes in estrogen-modulated transgenic mice

Jarred, Renea Anne; McPherson, Stephen; Bianco, Joseph; Couse, John F.; Korach, Kenneth S.; Risbridger, Gail P.

doi:10.1016/s1043-2760(02)00575-1

Cited by 46 publications

(36 citation statements)

References 44 publications

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“…Importantly, CYP19A1 encodes for the enzyme required for estrogen biosynthesis, the aromatase. If the role of CYP19A1 remains unclear to date regarding BPH pathophysiology, the knockout of this gene in mice elevated the circulating testosterone levels and caused enlargement of their prostates, but did not cause the mice to develop prostate cancer, [33,34], in support of a link between the estrogen signaling pathway to prostate physiology and pathophysiology. One hypothesis could be that a modification of CYP19A1 function may result in an imbalance between estrogens and androgen levels, thus influencing prostate volume.…”

Section: Discussionmentioning

confidence: 99%

Correlation between prostate volume and single nucleotide polymorphisms implicated in the steroid pathway

et al. 2016

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Section: Discussionmentioning

confidence: 99%

Correlation between prostate volume and single nucleotide polymorphisms implicated in the steroid pathway

et al. 2016

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“…ERb is expressed at high levels in normal prostate epithelium, while it is lost within prostate cancer cells (Lau et al, 2000;Horvath et al, 2001;Leav et al, 2001;Pasquali et al, 2001a,b;Bardin et al, 2004). The administration of phytoestrogens or estrogen-like substances activating ERb reduced proliferation in in vitro cell lines, and the development of prostate cancer in animals models (MentorMarcel et al, 2001;Jarred et al, 2002;McPherson et al, 2007). The present study demonstrated that both transcriptional regulation and non-genomic signals are activated by RAL.…”

Section: Discussionmentioning

confidence: 99%

Raloxifene induces cell death and inhibits proliferation through multiple signaling pathways in prostate cancer cells expressing different levels of estrogen receptorα and β

Rossi

Bellastella

Rosa

et al. 2011

Journal Cellular Physiology

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Raloxifene (RAL), a selective estrogen receptor (ER) modulator (SERM) seems to induce apoptosis in both androgen-dependent and -independent prostate cell (PC) lines via activation of ERβ and an antagonistic effect on ERα. In this study, we evaluated the effects of RAL on epithelial PC growth using the two following in vitro models: the androgen-dependent cell line EPN which expressed both ERs; and a stabilized epithelial cell line derived from a prostate cancer specimen (CPEC), which expressed low levels of ERβ and lacked ERα. In EPN cells, there was an increase in the pre-G1 apoptotic peak and a reduction in the S phase of the cell cycle with G0/G1 arrest after E2 or RAL treatment; bcl-2 mRNA and Bcl-2 protein levels were significantly reduced, while activated caspase-3 and Par-4 levels increased significantly after either E2 or RAL treatment; in addition, c-myc transcript was inhibited after 10(-6) M RAL treatment. A dose-dependent increase of metallothionein II gene RNA level was also induced by RAL in EPN. In CPEC, there was only a weak apoptotic peak associated with caspase-3 activation and Par-4 increase after either E2 or RAL treatment; while c-myc transcript level increased. RAL induced a rapid but transient phosphorylation of ERK 1/2 in EPN cells but generated a sustained effect in CPEC. These findings suggest that RAL effects on PC growth control in vitro are cell-specific, depending on ERβ or ERβ/ERα relative expression levels. Moreover, this study demonstrated that RAL affected both transcriptional regulation and non-genomic signals, which resulted in the modulation of multiple signaling pathways of apoptosis and of cell cycle progression.

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“…This compound (8β-VE2) has proven selectivity and was previously used to dissect the physiological roles of ERα and ERβ in vivo in bone, cardiovascular, and metabolic studies (14)(15)(16)(17)(18). To circumvent the use of a specific ERβ knock-out mouse model because of reported variation in prostatic phenotypes from different colonies (19), we used aromatase knock-out (ArKO) mice that lack endogenous estrogen ligands but express functional ERs (20), thus obviating any confounding action of ER activation by endogenous ligands. Using these mice, we compared the cellular targets and mechanism of action of ERβ agonist to castration.…”

mentioning

confidence: 99%

Estrogen receptor–β activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFα mediated

McPherson

Hussain

Balanathan

et al. 2010

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

185

147

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Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent diseases commonly treated by inhibiting androgen action. However, androgen ablation or castration fail to target androgen-independent cells implicated in disease etiology and recurrence. Mechanistically different to castration, this study shows beneficial proapoptotic actions of estrogen receptor–β (ERβ) in BPH and PCa. ERβ agonist induces apoptosis in prostatic stromal, luminal and castrate-resistant basal epithelial cells of estrogen-deficient aromatase knock-out mice. This occurs via extrinsic (caspase-8) pathways, without reducing serum hormones, and perturbs the regenerative capacity of the epithelium. TNFα knock-out mice fail to respond to ERβ agonist, demonstrating the requirement for TNFα signaling. In human tissues, ERβ agonist induces apoptosis in stroma and epithelium of xenografted BPH specimens, including in the CD133 + enriched putative stem/progenitor cells isolated from BPH-1 cells in vitro. In PCa, ERβ causes apoptosis in Gleason Grade 7 xenografted tissues and androgen-independent cells lines (PC3 and DU145) via caspase-8. These data provide evidence of the beneficial effects of ERβ agonist on epithelium and stroma of BPH, as well as androgen-independent tumor cells implicated in recurrent disease. Our data are indicative of the therapeutic potential of ERβ agonist for treatment of PCa and/or BPH with or without androgen withdrawal.

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Prostate phenotypes in estrogen-modulated transgenic mice

Cited by 46 publications

References 44 publications

Correlation between prostate volume and single nucleotide polymorphisms implicated in the steroid pathway

Correlation between prostate volume and single nucleotide polymorphisms implicated in the steroid pathway

Raloxifene induces cell death and inhibits proliferation through multiple signaling pathways in prostate cancer cells expressing different levels of estrogen receptorα and β

Estrogen receptor–β activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFα mediated

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