Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity

Itsuhiro Takizawa, Mitchell G Lawrence, Preetika Balanathan, Richard Rebello, Helen B Pearson, Elika Garg, John S Pedersen, Normand Pouliot, Robert Nadon, Matthew J Watt, Renea A Taylor, Patrick O Humbert, Ivan Topisirovic, Ola Larsson, Gail P Risbridger, Luc Furic

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Abstract

While high doses of estrogen, in combination with androgens, can initiate prostate cancer (PCa) via activation of the estrogen receptor alpha (ERalpha), the role of ERalpha in PCa cells within established tumors is largely unknown. Here we show that expression of ERalpha is increased in high grade human PCa. Similarly, ERalpha is elevated in mouse models of aggressive PCa driven by MYC overexpression or deletion of PTEN. Within the prostate of PTEN-deficient mice, there is a progressive pattern of ERalpha expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This expression significantly correlates with the proliferation marker Ki67. Furthermore, in vitro knockdown of ERalpha in cells derived from PTEN-deficient tumors causes a significant and sustained decrease in proliferation. Depletion of ERalpha also reduces the activity of the PI3K and MAPK pathways, both downstream targets of non-genomic ERalpha action. Finally, ERalpha knockdown reduces the levels of the MYC protein and lowers the sensitivity of cellular proliferation to glucose withdrawal, which correlates with decreased expression of the glucose transporter GLUT1. Collectively, these results demonstrate that ERalpha orchestrates proliferation and metabolism to promote the neoplastic growth of PCa cells.
Original languageEnglish
Pages (from-to)604 - 616
Number of pages13
JournalOncotarget
Volume6
Issue number2
DOIs
Publication statusPublished - 2015

Cite this

Takizawa, Itsuhiro ; Lawrence, Mitchell G ; Balanathan, Preetika ; Rebello, Richard ; Pearson, Helen B ; Garg, Elika ; Pedersen, John S ; Pouliot, Normand ; Nadon, Robert ; Watt, Matthew J ; Taylor, Renea A ; Humbert, Patrick O ; Topisirovic, Ivan ; Larsson, Ola ; Risbridger, Gail P ; Furic, Luc. / Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity. In: Oncotarget. 2015 ; Vol. 6, No. 2. pp. 604 - 616.
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abstract = "While high doses of estrogen, in combination with androgens, can initiate prostate cancer (PCa) via activation of the estrogen receptor alpha (ERalpha), the role of ERalpha in PCa cells within established tumors is largely unknown. Here we show that expression of ERalpha is increased in high grade human PCa. Similarly, ERalpha is elevated in mouse models of aggressive PCa driven by MYC overexpression or deletion of PTEN. Within the prostate of PTEN-deficient mice, there is a progressive pattern of ERalpha expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This expression significantly correlates with the proliferation marker Ki67. Furthermore, in vitro knockdown of ERalpha in cells derived from PTEN-deficient tumors causes a significant and sustained decrease in proliferation. Depletion of ERalpha also reduces the activity of the PI3K and MAPK pathways, both downstream targets of non-genomic ERalpha action. Finally, ERalpha knockdown reduces the levels of the MYC protein and lowers the sensitivity of cellular proliferation to glucose withdrawal, which correlates with decreased expression of the glucose transporter GLUT1. Collectively, these results demonstrate that ERalpha orchestrates proliferation and metabolism to promote the neoplastic growth of PCa cells.",
author = "Itsuhiro Takizawa and Lawrence, {Mitchell G} and Preetika Balanathan and Richard Rebello and Pearson, {Helen B} and Elika Garg and Pedersen, {John S} and Normand Pouliot and Robert Nadon and Watt, {Matthew J} and Taylor, {Renea A} and Humbert, {Patrick O} and Ivan Topisirovic and Ola Larsson and Risbridger, {Gail P} and Luc Furic",
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Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity. / Takizawa, Itsuhiro; Lawrence, Mitchell G; Balanathan, Preetika; Rebello, Richard; Pearson, Helen B; Garg, Elika; Pedersen, John S; Pouliot, Normand; Nadon, Robert; Watt, Matthew J; Taylor, Renea A; Humbert, Patrick O; Topisirovic, Ivan; Larsson, Ola; Risbridger, Gail P; Furic, Luc.

In: Oncotarget, Vol. 6, No. 2, 2015, p. 604 - 616.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity

AU - Takizawa, Itsuhiro

AU - Lawrence, Mitchell G

AU - Balanathan, Preetika

AU - Rebello, Richard

AU - Pearson, Helen B

AU - Garg, Elika

AU - Pedersen, John S

AU - Pouliot, Normand

AU - Nadon, Robert

AU - Watt, Matthew J

AU - Taylor, Renea A

AU - Humbert, Patrick O

AU - Topisirovic, Ivan

AU - Larsson, Ola

AU - Risbridger, Gail P

AU - Furic, Luc

PY - 2015

Y1 - 2015

N2 - While high doses of estrogen, in combination with androgens, can initiate prostate cancer (PCa) via activation of the estrogen receptor alpha (ERalpha), the role of ERalpha in PCa cells within established tumors is largely unknown. Here we show that expression of ERalpha is increased in high grade human PCa. Similarly, ERalpha is elevated in mouse models of aggressive PCa driven by MYC overexpression or deletion of PTEN. Within the prostate of PTEN-deficient mice, there is a progressive pattern of ERalpha expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This expression significantly correlates with the proliferation marker Ki67. Furthermore, in vitro knockdown of ERalpha in cells derived from PTEN-deficient tumors causes a significant and sustained decrease in proliferation. Depletion of ERalpha also reduces the activity of the PI3K and MAPK pathways, both downstream targets of non-genomic ERalpha action. Finally, ERalpha knockdown reduces the levels of the MYC protein and lowers the sensitivity of cellular proliferation to glucose withdrawal, which correlates with decreased expression of the glucose transporter GLUT1. Collectively, these results demonstrate that ERalpha orchestrates proliferation and metabolism to promote the neoplastic growth of PCa cells.

AB - While high doses of estrogen, in combination with androgens, can initiate prostate cancer (PCa) via activation of the estrogen receptor alpha (ERalpha), the role of ERalpha in PCa cells within established tumors is largely unknown. Here we show that expression of ERalpha is increased in high grade human PCa. Similarly, ERalpha is elevated in mouse models of aggressive PCa driven by MYC overexpression or deletion of PTEN. Within the prostate of PTEN-deficient mice, there is a progressive pattern of ERalpha expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This expression significantly correlates with the proliferation marker Ki67. Furthermore, in vitro knockdown of ERalpha in cells derived from PTEN-deficient tumors causes a significant and sustained decrease in proliferation. Depletion of ERalpha also reduces the activity of the PI3K and MAPK pathways, both downstream targets of non-genomic ERalpha action. Finally, ERalpha knockdown reduces the levels of the MYC protein and lowers the sensitivity of cellular proliferation to glucose withdrawal, which correlates with decreased expression of the glucose transporter GLUT1. Collectively, these results demonstrate that ERalpha orchestrates proliferation and metabolism to promote the neoplastic growth of PCa cells.

UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359242/pdf/oncotarget-06-604.pdf

U2 - 10.18632/oncotarget.2820

DO - 10.18632/oncotarget.2820

M3 - Article

VL - 6

SP - 604

EP - 616

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 2

ER -