A feedback loop between androgen receptor and ERK signaling in estrogen receptor-negative breast cancer

Chia, Kee Ming, Liu, Ji, Francis, Glenn D. and Naderi, Ali (2011) A feedback loop between androgen receptor and ERK signaling in estrogen receptor-negative breast cancer. Neoplasia, 13 2: 154-166. doi:10.1593/neo.101324

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Author Chia, Kee Ming
Liu, Ji
Francis, Glenn D.
Naderi, Ali
Title A feedback loop between androgen receptor and ERK signaling in estrogen receptor-negative breast cancer
Journal name Neoplasia   Check publisher's open access policy
ISSN 1522-8002
1476-5586
Publication date 2011-02-01
Sub-type Article (original research)
DOI 10.1593/neo.101324
Open Access Status DOI
Volume 13
Issue 2
Start page 154
End page 166
Total pages 13
Place of publication Gonic NH, United States
Publisher Neoplasia Press
Collection year 2012
Language eng
Formatted abstract
Estrogen receptor (ER)-negative breast cancer is heterogeneous, and the biology of this disease has remained poorly understood. Molecular apocrine is a subtype of ER-negative breast cancer that is characterized by the overexpression of steroid-response genes such as AR and a high rate of ErbB2 amplification. In this study, we have identified a positive feedback loop between the AR and extracellular signal-regulated kinase (ERK) signaling pathways in molecular apocrine breast cancer. In this process, AR regulates ERK phosphorylation and kinase activity. In addition, AR inhibition results in the down-regulation of ERK target proteins phospho-RSK1, phospho-Elk-1, and c-Fos using an in vivo molecular apocrine model. Furthermore, we show that AR-mediated induction of ERK requires ErbB2, and AR activity, in turn, regulates ErbB2 expression as an AR target gene. These findings suggest that ErbB2 is an upstream connector between the AR and ERK signaling pathways. Another feature of this feedback loop is an ERK-mediated regulation of AR. In this respect, the inhibition of ERK phosphorylation reduces AR expression and CREB1-mediated transcriptional regulation of AR acts as a downstream connector between the AR and ERK signaling pathways in molecular apocrine cells. Finally, we demonstrate that AR-positive staining is associated with the overexpression of ERK signaling targets phospho-Elk-1 and c-Fos in ER-negative breast tumors, which further supports a cross-regulation between the AR and ERK signaling pathways in molecular apocrine subtype. This study demonstrates an AR-ERK feedback loop in ER-negative breast cancer with significant biologic and therapeutic implications in this disease.
Keyword Prostate-cancer
Induced phosphorylation
Lncap cells
Map kinase
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
UQ Diamantina Institute Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 33 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 38 times in Scopus Article | Citations
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Created: Sun, 13 Mar 2011, 10:07:54 EST