PMID- 23950888
OWN - NLM
STAT- MEDLINE
DCOM- 20140303
LR  - 20240320
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 8
DP  - 2013
TI  - MEK5/ERK5 signaling suppresses estrogen receptor expression and promotes 
      hormone-independent tumorigenesis.
PG  - e69291
LID - 10.1371/journal.pone.0069291 [doi]
LID - e69291
AB  - Endocrine resistance and metastatic progression are primary causes of treatment 
      failure in breast cancer. While mitogen activated protein kinases (MAPKs) are 
      known to promote ligand-independent cell growth, the role of the MEK5-ERK5 
      pathway in the progression of clinical breast carcinoma remains poorly 
      understood. Here, we demonstrated increased ERK5 activation in 30 of 39 (76.9%) 
      clinical tumor samples, as well as across breast cancer cell systems. 
      Overexpression of MEK5 in MCF-7 cells promoted both hormone-dependent and 
      hormone-independent tumorigenesis in vitro and in vivo and conferred endocrine 
      therapy resistance to previously sensitive breast cancer cells. Expression of 
      MEK5 suppressed estrogen receptor (ER)alpha, but not ER-beta protein levels, and 
      abrogated downstream estrogen response element (ERE) transcriptional activity and 
      ER-mediated gene transcription. Global gene expression changes associated with 
      upregulation of MEK5 included increased activation of ER-alpha independent growth 
      signaling pathways and promotion of epithelial-to-mesenchymal transition (EMT) 
      markers. Taken together, our findings show that the MEK5-ERK5 pathway mediates 
      progression to an ER(-), mesenchymal and endocrine therapy resistant phenotype. 
      Given the need for new clinical therapeutic targets, our results demonstrate the 
      therapeutic potential of targeting the MEK5-ERK5 pathway in breast cancer.
FAU - Antoon, James W
AU  - Antoon JW
AD  - Department of Pharmacology, Tulane University School of Medicine, New Orleans, 
      Louisiana, USA.
FAU - Martin, Elizabeth C
AU  - Martin EC
FAU - Lai, Rongye
AU  - Lai R
FAU - Salvo, Virgilo A
AU  - Salvo VA
FAU - Tang, Yan
AU  - Tang Y
FAU - Nitzchke, Ashley M
AU  - Nitzchke AM
FAU - Elliott, Steven
AU  - Elliott S
FAU - Nam, Seung Yoon
AU  - Nam SY
FAU - Xiong, Wei
AU  - Xiong W
FAU - Rhodes, Lyndsay V
AU  - Rhodes LV
FAU - Collins-Burow, Bridgette
AU  - Collins-Burow B
FAU - David, Odile
AU  - David O
FAU - Wang, Guandi
AU  - Wang G
FAU - Shan, Bin
AU  - Shan B
FAU - Beckman, Barbara S
AU  - Beckman BS
FAU - Nephew, Kenneth P
AU  - Nephew KP
FAU - Burow, Matthew E
AU  - Burow ME
LA  - eng
GR  - R01 CA125806/CA/NCI NIH HHS/United States
GR  - U54 CA113001/CA/NCI NIH HHS/United States
GR  - CA125806/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130809
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antineoplastic Agents, Hormonal)
RN  - 0 (ESR1 protein, human)
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (Estrogens)
RN  - 0 (RNA, Small Interfering)
RN  - 22X328QOC4 (Fulvestrant)
RN  - 4TI98Z838E (Estradiol)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 7)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 5)
RN  - EC 2.7.12.2 (MAP2K5 protein, human)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Hormonal/pharmacology
MH  - Breast Neoplasms/*genetics/metabolism/pathology
MH  - Carcinogenesis/genetics/metabolism/pathology
MH  - Carcinoma/*genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/drug effects/genetics
MH  - Epithelial-Mesenchymal Transition/genetics
MH  - Estradiol/analogs & derivatives/pharmacology
MH  - Estrogen Receptor alpha/*genetics/metabolism
MH  - Estrogens/metabolism
MH  - Female
MH  - Fulvestrant
MH  - Gene Expression Profiling
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - MAP Kinase Kinase 5/*genetics/metabolism
MH  - Mice
MH  - Mitogen-Activated Protein Kinase 7/antagonists & inhibitors/*genetics/metabolism
MH  - Neoplasms, Experimental
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Signal Transduction
PMC - PMC3739787
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/08/21 06:00
MHDA- 2014/03/04 06:00
PMCR- 2013/08/09
CRDT- 2013/08/17 06:00
PHST- 2012/05/15 00:00 [received]
PHST- 2013/06/12 00:00 [accepted]
PHST- 2013/08/17 06:00 [entrez]
PHST- 2013/08/21 06:00 [pubmed]
PHST- 2014/03/04 06:00 [medline]
PHST- 2013/08/09 00:00 [pmc-release]
AID - PONE-D-12-13950 [pii]
AID - 10.1371/journal.pone.0069291 [doi]
PST - epublish
SO  - PLoS One. 2013 Aug 9;8(8):e69291. doi: 10.1371/journal.pone.0069291. eCollection 
      2013.