Mechanisms of dihydrotestosterone action on resveratrolinduced anti-proliferation in breast cancer cells with different ER status

Yu Tang Chin, Sheng Huei Yang, Tung Cheng Chang, Chun A. Changou, Hsuan Yu Lai, Earl Fu, Wei Chun HuangFu, Paul J. Davis, Hung Yun Lin, Leroy F. Liu

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Dihydrotestosterone (DHT) has been shown to promote breast cancer growth via different mechanisms. In addition to binding to ERa, the DHT membrane receptor exists on integrin avβ3. Resveratrol induces p53-dependent apoptosis via plasma membrane integrin avβ3. Resveratrol and DHT signals are both transduced by activated ERK1/2; however, DHT promotes cell proliferation in cancer cells, whereas resveratrol is proapoptotic. In this study, we examined the mechanism by which DHT inhibits resveratrolinduced apoptosis in human ERa positive (MCF-7) and negative (MDA-MB-231) breast cancer cells. DHT inhibited resveratrol-stimulated phosphorylation of Ser-15 of p53 in a concentration-dependent manner. These effects of DHT on resveratrol action were blocked by an ERa antagonist, ICI 182,780, in MCF-7 breast cancer cells. DHT inhibited resveratrol-induced nuclear complex of p53-COX-2 formation which is required p53- dependent apoptosis. ChIP studies of COX-2/p53 binding to DNA and expression of p53-responsive genes indicated that DHT inhibited resveratrol-induced p53-directed transcriptional activity. In addition, DHT did inhibit resveratrol-induced COX-2/p53- dependent gene expression. These results suggest that DHT inhibits p53-dependent apoptosis in breast cancer cells by interfering with nuclear COX-2 accumulation which is essential for stimulation of apoptotic pathways. Thus, the surface receptor sites for resveratrol and DHT are discrete and activate ERK1/2-dependent downstream effects on apoptosis that are distinctive. These studies provide new insights into the antagonizing effects of resveratrol versus DHT, an important step toward better understanding and eventually treating breast cancer. It also indicates the complex pathways by which apoptosis is induced by resveratrol in DHT-depleted and -repleted environments.

Original languageEnglish
Pages (from-to)35866-35879
Number of pages14
JournalOncotarget
Volume6
Issue number34
DOIs
Publication statusPublished - 2015

Fingerprint

Dihydrotestosterone
Breast Neoplasms
Apoptosis
p53 Genes
Integrins
resveratrol
Androgen Receptors

Keywords

  • Breast cancer
  • DHT
  • Estrogen receptor-a
  • Integrin avb3
  • Resveratrol

ASJC Scopus subject areas

  • Oncology

Cite this

Mechanisms of dihydrotestosterone action on resveratrolinduced anti-proliferation in breast cancer cells with different ER status. / Chin, Yu Tang; Yang, Sheng Huei; Chang, Tung Cheng; Changou, Chun A.; Lai, Hsuan Yu; Fu, Earl; HuangFu, Wei Chun; Davis, Paul J.; Lin, Hung Yun; Liu, Leroy F.

In: Oncotarget, Vol. 6, No. 34, 2015, p. 35866-35879.

Research output: Contribution to journalArticle

Chin, Yu Tang ; Yang, Sheng Huei ; Chang, Tung Cheng ; Changou, Chun A. ; Lai, Hsuan Yu ; Fu, Earl ; HuangFu, Wei Chun ; Davis, Paul J. ; Lin, Hung Yun ; Liu, Leroy F. / Mechanisms of dihydrotestosterone action on resveratrolinduced anti-proliferation in breast cancer cells with different ER status. In: Oncotarget. 2015 ; Vol. 6, No. 34. pp. 35866-35879.
@article{e054f0e8aa36457faa08da3fec2cfd67,
title = "Mechanisms of dihydrotestosterone action on resveratrolinduced anti-proliferation in breast cancer cells with different ER status",
abstract = "Dihydrotestosterone (DHT) has been shown to promote breast cancer growth via different mechanisms. In addition to binding to ERa, the DHT membrane receptor exists on integrin avβ3. Resveratrol induces p53-dependent apoptosis via plasma membrane integrin avβ3. Resveratrol and DHT signals are both transduced by activated ERK1/2; however, DHT promotes cell proliferation in cancer cells, whereas resveratrol is proapoptotic. In this study, we examined the mechanism by which DHT inhibits resveratrolinduced apoptosis in human ERa positive (MCF-7) and negative (MDA-MB-231) breast cancer cells. DHT inhibited resveratrol-stimulated phosphorylation of Ser-15 of p53 in a concentration-dependent manner. These effects of DHT on resveratrol action were blocked by an ERa antagonist, ICI 182,780, in MCF-7 breast cancer cells. DHT inhibited resveratrol-induced nuclear complex of p53-COX-2 formation which is required p53- dependent apoptosis. ChIP studies of COX-2/p53 binding to DNA and expression of p53-responsive genes indicated that DHT inhibited resveratrol-induced p53-directed transcriptional activity. In addition, DHT did inhibit resveratrol-induced COX-2/p53- dependent gene expression. These results suggest that DHT inhibits p53-dependent apoptosis in breast cancer cells by interfering with nuclear COX-2 accumulation which is essential for stimulation of apoptotic pathways. Thus, the surface receptor sites for resveratrol and DHT are discrete and activate ERK1/2-dependent downstream effects on apoptosis that are distinctive. These studies provide new insights into the antagonizing effects of resveratrol versus DHT, an important step toward better understanding and eventually treating breast cancer. It also indicates the complex pathways by which apoptosis is induced by resveratrol in DHT-depleted and -repleted environments.",
keywords = "Breast cancer, DHT, Estrogen receptor-a, Integrin avb3, Resveratrol",
author = "Chin, {Yu Tang} and Yang, {Sheng Huei} and Chang, {Tung Cheng} and Changou, {Chun A.} and Lai, {Hsuan Yu} and Earl Fu and HuangFu, {Wei Chun} and Davis, {Paul J.} and Lin, {Hung Yun} and Liu, {Leroy F.}",
year = "2015",
doi = "10.18632/oncotarget.5482",
language = "English",
volume = "6",
pages = "35866--35879",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "34",

}

TY - JOUR

T1 - Mechanisms of dihydrotestosterone action on resveratrolinduced anti-proliferation in breast cancer cells with different ER status

AU - Chin, Yu Tang

AU - Yang, Sheng Huei

AU - Chang, Tung Cheng

AU - Changou, Chun A.

AU - Lai, Hsuan Yu

AU - Fu, Earl

AU - HuangFu, Wei Chun

AU - Davis, Paul J.

AU - Lin, Hung Yun

AU - Liu, Leroy F.

PY - 2015

Y1 - 2015

N2 - Dihydrotestosterone (DHT) has been shown to promote breast cancer growth via different mechanisms. In addition to binding to ERa, the DHT membrane receptor exists on integrin avβ3. Resveratrol induces p53-dependent apoptosis via plasma membrane integrin avβ3. Resveratrol and DHT signals are both transduced by activated ERK1/2; however, DHT promotes cell proliferation in cancer cells, whereas resveratrol is proapoptotic. In this study, we examined the mechanism by which DHT inhibits resveratrolinduced apoptosis in human ERa positive (MCF-7) and negative (MDA-MB-231) breast cancer cells. DHT inhibited resveratrol-stimulated phosphorylation of Ser-15 of p53 in a concentration-dependent manner. These effects of DHT on resveratrol action were blocked by an ERa antagonist, ICI 182,780, in MCF-7 breast cancer cells. DHT inhibited resveratrol-induced nuclear complex of p53-COX-2 formation which is required p53- dependent apoptosis. ChIP studies of COX-2/p53 binding to DNA and expression of p53-responsive genes indicated that DHT inhibited resveratrol-induced p53-directed transcriptional activity. In addition, DHT did inhibit resveratrol-induced COX-2/p53- dependent gene expression. These results suggest that DHT inhibits p53-dependent apoptosis in breast cancer cells by interfering with nuclear COX-2 accumulation which is essential for stimulation of apoptotic pathways. Thus, the surface receptor sites for resveratrol and DHT are discrete and activate ERK1/2-dependent downstream effects on apoptosis that are distinctive. These studies provide new insights into the antagonizing effects of resveratrol versus DHT, an important step toward better understanding and eventually treating breast cancer. It also indicates the complex pathways by which apoptosis is induced by resveratrol in DHT-depleted and -repleted environments.

AB - Dihydrotestosterone (DHT) has been shown to promote breast cancer growth via different mechanisms. In addition to binding to ERa, the DHT membrane receptor exists on integrin avβ3. Resveratrol induces p53-dependent apoptosis via plasma membrane integrin avβ3. Resveratrol and DHT signals are both transduced by activated ERK1/2; however, DHT promotes cell proliferation in cancer cells, whereas resveratrol is proapoptotic. In this study, we examined the mechanism by which DHT inhibits resveratrolinduced apoptosis in human ERa positive (MCF-7) and negative (MDA-MB-231) breast cancer cells. DHT inhibited resveratrol-stimulated phosphorylation of Ser-15 of p53 in a concentration-dependent manner. These effects of DHT on resveratrol action were blocked by an ERa antagonist, ICI 182,780, in MCF-7 breast cancer cells. DHT inhibited resveratrol-induced nuclear complex of p53-COX-2 formation which is required p53- dependent apoptosis. ChIP studies of COX-2/p53 binding to DNA and expression of p53-responsive genes indicated that DHT inhibited resveratrol-induced p53-directed transcriptional activity. In addition, DHT did inhibit resveratrol-induced COX-2/p53- dependent gene expression. These results suggest that DHT inhibits p53-dependent apoptosis in breast cancer cells by interfering with nuclear COX-2 accumulation which is essential for stimulation of apoptotic pathways. Thus, the surface receptor sites for resveratrol and DHT are discrete and activate ERK1/2-dependent downstream effects on apoptosis that are distinctive. These studies provide new insights into the antagonizing effects of resveratrol versus DHT, an important step toward better understanding and eventually treating breast cancer. It also indicates the complex pathways by which apoptosis is induced by resveratrol in DHT-depleted and -repleted environments.

KW - Breast cancer

KW - DHT

KW - Estrogen receptor-a

KW - Integrin avb3

KW - Resveratrol

UR - http://www.scopus.com/inward/record.url?scp=84946866409&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84946866409&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.5482

DO - 10.18632/oncotarget.5482

M3 - Article

C2 - 26456774

AN - SCOPUS:84946866409

VL - 6

SP - 35866

EP - 35879

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 34

ER -