Estrogen receptor-beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFalpha mediated

Stephen John McPherson, Shirin Hussain, Preetika Balanathan, Shelley Lee Hedwards, Birunthi Niranjan, Michael Grant, Upeksha Priyadarshani Chandrasiri, Roxanne Toivanen, Yuzhuo Wang, Renea Anne Taylor, Gail Petuna Risbridger

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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-beta (ERbeta) in BPH and PCa. ERbeta 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. TNFalpha knock-out mice fail to respond to ERbeta agonist, demonstrating the requirement for TNFalpha signaling. In human tissues, ERbeta 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, ERbeta 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 ERbeta 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 ERbeta agonist for treatment of PCa and/or BPH with or without androgen withdrawal.
Original languageEnglish
Pages (from-to)3123 - 3128
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume107
Issue number7
DOIs
Publication statusPublished - 2010

Cite this

McPherson, Stephen John ; Hussain, Shirin ; Balanathan, Preetika ; Hedwards, Shelley Lee ; Niranjan, Birunthi ; Grant, Michael ; Chandrasiri, Upeksha Priyadarshani ; Toivanen, Roxanne ; Wang, Yuzhuo ; Taylor, Renea Anne ; Risbridger, Gail Petuna. / Estrogen receptor-beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFalpha mediated. In: Proceedings of the National Academy of Sciences. 2010 ; Vol. 107, No. 7. pp. 3123 - 3128.
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abstract = "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-beta (ERbeta) in BPH and PCa. ERbeta 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. TNFalpha knock-out mice fail to respond to ERbeta agonist, demonstrating the requirement for TNFalpha signaling. In human tissues, ERbeta 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, ERbeta 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 ERbeta 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 ERbeta agonist for treatment of PCa and/or BPH with or without androgen withdrawal.",
author = "McPherson, {Stephen John} and Shirin Hussain and Preetika Balanathan and Hedwards, {Shelley Lee} and Birunthi Niranjan and Michael Grant and Chandrasiri, {Upeksha Priyadarshani} and Roxanne Toivanen and Yuzhuo Wang and Taylor, {Renea Anne} and Risbridger, {Gail Petuna}",
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Estrogen receptor-beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFalpha mediated. / McPherson, Stephen John; Hussain, Shirin; Balanathan, Preetika; Hedwards, Shelley Lee; Niranjan, Birunthi; Grant, Michael; Chandrasiri, Upeksha Priyadarshani; Toivanen, Roxanne; Wang, Yuzhuo; Taylor, Renea Anne; Risbridger, Gail Petuna.

In: Proceedings of the National Academy of Sciences, Vol. 107, No. 7, 2010, p. 3123 - 3128.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Estrogen receptor-beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFalpha mediated

AU - McPherson, Stephen John

AU - Hussain, Shirin

AU - Balanathan, Preetika

AU - Hedwards, Shelley Lee

AU - Niranjan, Birunthi

AU - Grant, Michael

AU - Chandrasiri, Upeksha Priyadarshani

AU - Toivanen, Roxanne

AU - Wang, Yuzhuo

AU - Taylor, Renea Anne

AU - Risbridger, Gail Petuna

PY - 2010

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N2 - 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-beta (ERbeta) in BPH and PCa. ERbeta 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. TNFalpha knock-out mice fail to respond to ERbeta agonist, demonstrating the requirement for TNFalpha signaling. In human tissues, ERbeta 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, ERbeta 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 ERbeta 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 ERbeta agonist for treatment of PCa and/or BPH with or without androgen withdrawal.

AB - 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-beta (ERbeta) in BPH and PCa. ERbeta 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. TNFalpha knock-out mice fail to respond to ERbeta agonist, demonstrating the requirement for TNFalpha signaling. In human tissues, ERbeta 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, ERbeta 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 ERbeta 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 ERbeta agonist for treatment of PCa and/or BPH with or without androgen withdrawal.

UR - http://www.pnas.org/content/107/7/3123.full.pdf+html

U2 - 10.1073/pnas.0905524107

DO - 10.1073/pnas.0905524107

M3 - Article

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 7

ER -