MP31-07 ESTROGEN RECEPTOR α REGULATES PROLIFERATION IN PTEN NULL PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 2014MP31-07 ESTROGEN RECEPTOR α REGULATES PROLIFERATION IN PTEN NULL PROSTATE CANCER Itsuhiro Takizawa, Mitchell Lawrence, Helen Pearson, John Pedersen, Normand Pouliot, Australian Prostate, Cancer BioResource, Patrick Humbert, Luc Furic, and Gail Risbridger Itsuhiro TakizawaItsuhiro Takizawa More articles by this author , Mitchell LawrenceMitchell Lawrence More articles by this author , Helen PearsonHelen Pearson More articles by this author , John PedersenJohn Pedersen More articles by this author , Normand PouliotNormand Pouliot More articles by this author , Australian ProstateAustralian Prostate More articles by this author , Cancer BioResourceCancer BioResource More articles by this author , Patrick HumbertPatrick Humbert More articles by this author , Luc FuricLuc Furic More articles by this author , and Gail RisbridgerGail Risbridger More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.916AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES High doses of estrogen, in combination with androgens, can initiate prostate cancer. This effect is attributed to the activity of the estrogen receptor α (ERα). Although it is well established that ERα stimulates proliferation via genomic and non-genomic activities in breast and ovarian cancer, relatively little is known about the functions of ERα in prostate cancer cells. We observed that ERα expression is up-regulated in high Gleason Score specimens of human prostate cancer. We also noted that the incidence and severity of tumours in PTEN conditional knockout mice with prostate-specific deletion of PTEN, correlates with the estrogen sensitivity of each lobe of the prostate. Therefore, we hypothesized that this model could be used to study the role of ERα in prostate cancer progression. METHODS Immunohistochemistry and stereology were used to quantify ERα and Ki67 expression in PTEN null mice. To assess the functional role of ERα, a cell line derived from a PTEN null tumour was treated with shRNA or TPSF, a non-competitive ERα antagonist. Rescue experiments with expression constructs for either full length ERα, capable of genomic and non-genomic actions, or membrane-only ERα, only able to trigger rapid non-genomic signalling, were used to determine the mechanism underlying ERα-regulated proliferation. RESULTS There was a dramatic increase in ERα expression in prostate tumours of PTEN null mice compared with normal prostates of control animals. Within the PTEN null prostate, there was a consistent pattern of ERα expression: low in benign glands, moderate in tumours within the dorsal, lateral and ventral lobes, and high in tumours within the anterior prostate. This pattern significantly correlated with the levels of the proliferative marker Ki67. There was also a significant correlation between ERα and Ki67 within individual malignant glands in the anterior prostate. In vitro knockdown of ERα attenuated the proliferation of PTEN null cells as did treatment with TPSF. Loss of ERα reduced the activity of both the PI3K and MAPK pathways and decreased MYC levels. This effect was reversed by re-expressing full-length or membrane-only ERα. CONCLUSIONS Collectively, these results demonstrate that ERα drives the proliferation of prostate cancer cells through classical genomic and rapid non-genomic signalling. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e324-e325 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Itsuhiro Takizawa More articles by this author Mitchell Lawrence More articles by this author Helen Pearson More articles by this author John Pedersen More articles by this author Normand Pouliot More articles by this author Australian Prostate More articles by this author Cancer BioResource More articles by this author Patrick Humbert More articles by this author Luc Furic More articles by this author Gail Risbridger More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...