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Wild‐type and specific mutant androgen receptor mediates transcription via 17β‐estradiol in sex hormone‐sensitive cancer cells

We previously encountered regulatory processes wherein dihydrotestosterone (DHT) exerted its inhibitory effect on parathyroid hormone‐related protein (PTHrP) gene repression through the estrogen receptor (ER)α, but not the androgen receptor (AR), in breast cancer MCF‐7 cells. Here, we investigated w...

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Autores principales: Susa, Takao, Ikaga, Reina, Kajitani, Takashi, Iizuka, Masayoshi, Okinaga, Hiroko, Tamamori‐Adachi, Mimi, Okazaki, Tomoki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680109/
https://www.ncbi.nlm.nih.gov/pubmed/25536295
http://dx.doi.org/10.1002/jcp.24906
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author Susa, Takao
Ikaga, Reina
Kajitani, Takashi
Iizuka, Masayoshi
Okinaga, Hiroko
Tamamori‐Adachi, Mimi
Okazaki, Tomoki
author_facet Susa, Takao
Ikaga, Reina
Kajitani, Takashi
Iizuka, Masayoshi
Okinaga, Hiroko
Tamamori‐Adachi, Mimi
Okazaki, Tomoki
author_sort Susa, Takao
collection PubMed
description We previously encountered regulatory processes wherein dihydrotestosterone (DHT) exerted its inhibitory effect on parathyroid hormone‐related protein (PTHrP) gene repression through the estrogen receptor (ER)α, but not the androgen receptor (AR), in breast cancer MCF‐7 cells. Here, we investigated whether such aberrant ligand‐nuclear receptor (NR) interaction is present in prostate cancer LNCaP cells. First, we confirmed that LNCaP cells expressed large amounts of AR at negligible levels of ERα/β or progesterone receptor. Both suppression of PTHrP and activation of prostate‐specific antigen genes were observed after independent administration of 17β‐estradiol (E2), DHT, or R5020. Consistent with the notion that the LNCaP AR lost its ligand specificity due to a mutation (Thr‐Ala877), experiments with siRNA targeting the respective NR revealed that the AR monopolized the role of the mediator of shared hormone‐dependent regulation, which was invariably associated with nuclear translocation of this mutant AR. Microarray analysis of gene regulation by DHT, E2, or R5020 disclosed that more than half of the genes downstream of the AR (Thr‐Ala877) overlapped in the LNCaP cells. Of particular interest, we realized that the AR (wild‐type [wt]) and AR (Thr‐Ala877) were equally responsible for the E2‐AR interactions. Fluorescence microscopy experiments demonstrated that both EGFP‐AR (wt) and EGFP‐AR (Thr‐Ala877) were exclusively localized within the nucleus after E2 or DHT treatment. Furthermore, reporter assays revealed that some other cancer cells exhibited aberrant E2‐AR (wt) signaling similar to that in the LNCaP cells. We herein postulate the presence of entangled interactions between wt AR and E2 in certain hormone‐sensitive cancer cells. J. Cell. Physiol. 230: 1594–1606, 2015. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.
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spelling pubmed-66801092019-08-09 Wild‐type and specific mutant androgen receptor mediates transcription via 17β‐estradiol in sex hormone‐sensitive cancer cells Susa, Takao Ikaga, Reina Kajitani, Takashi Iizuka, Masayoshi Okinaga, Hiroko Tamamori‐Adachi, Mimi Okazaki, Tomoki J Cell Physiol Original Research Articles We previously encountered regulatory processes wherein dihydrotestosterone (DHT) exerted its inhibitory effect on parathyroid hormone‐related protein (PTHrP) gene repression through the estrogen receptor (ER)α, but not the androgen receptor (AR), in breast cancer MCF‐7 cells. Here, we investigated whether such aberrant ligand‐nuclear receptor (NR) interaction is present in prostate cancer LNCaP cells. First, we confirmed that LNCaP cells expressed large amounts of AR at negligible levels of ERα/β or progesterone receptor. Both suppression of PTHrP and activation of prostate‐specific antigen genes were observed after independent administration of 17β‐estradiol (E2), DHT, or R5020. Consistent with the notion that the LNCaP AR lost its ligand specificity due to a mutation (Thr‐Ala877), experiments with siRNA targeting the respective NR revealed that the AR monopolized the role of the mediator of shared hormone‐dependent regulation, which was invariably associated with nuclear translocation of this mutant AR. Microarray analysis of gene regulation by DHT, E2, or R5020 disclosed that more than half of the genes downstream of the AR (Thr‐Ala877) overlapped in the LNCaP cells. Of particular interest, we realized that the AR (wild‐type [wt]) and AR (Thr‐Ala877) were equally responsible for the E2‐AR interactions. Fluorescence microscopy experiments demonstrated that both EGFP‐AR (wt) and EGFP‐AR (Thr‐Ala877) were exclusively localized within the nucleus after E2 or DHT treatment. Furthermore, reporter assays revealed that some other cancer cells exhibited aberrant E2‐AR (wt) signaling similar to that in the LNCaP cells. We herein postulate the presence of entangled interactions between wt AR and E2 in certain hormone‐sensitive cancer cells. J. Cell. Physiol. 230: 1594–1606, 2015. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc. John Wiley and Sons Inc. 2015-07 2015-03-27 /pmc/articles/PMC6680109/ /pubmed/25536295 http://dx.doi.org/10.1002/jcp.24906 Text en © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Research Articles
Susa, Takao
Ikaga, Reina
Kajitani, Takashi
Iizuka, Masayoshi
Okinaga, Hiroko
Tamamori‐Adachi, Mimi
Okazaki, Tomoki
Wild‐type and specific mutant androgen receptor mediates transcription via 17β‐estradiol in sex hormone‐sensitive cancer cells
title Wild‐type and specific mutant androgen receptor mediates transcription via 17β‐estradiol in sex hormone‐sensitive cancer cells
title_full Wild‐type and specific mutant androgen receptor mediates transcription via 17β‐estradiol in sex hormone‐sensitive cancer cells
title_fullStr Wild‐type and specific mutant androgen receptor mediates transcription via 17β‐estradiol in sex hormone‐sensitive cancer cells
title_full_unstemmed Wild‐type and specific mutant androgen receptor mediates transcription via 17β‐estradiol in sex hormone‐sensitive cancer cells
title_short Wild‐type and specific mutant androgen receptor mediates transcription via 17β‐estradiol in sex hormone‐sensitive cancer cells
title_sort wild‐type and specific mutant androgen receptor mediates transcription via 17β‐estradiol in sex hormone‐sensitive cancer cells
topic Original Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680109/
https://www.ncbi.nlm.nih.gov/pubmed/25536295
http://dx.doi.org/10.1002/jcp.24906
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