PMID- 24374826
OWN - NLM
STAT- MEDLINE
DCOM- 20140804
LR  - 20211021
IS  - 1460-2180 (Electronic)
IS  - 0143-3334 (Print)
IS  - 0143-3334 (Linking)
VI  - 35
IP  - 6
DP  - 2014 Jun
TI  - Estrogen receptor alpha in cancer-associated fibroblasts suppresses prostate cancer 
      invasion via modulation of thrombospondin 2 and matrix metalloproteinase 3.
PG  - 1301-9
LID - 10.1093/carcin/bgt488 [doi]
AB  - The prostate cancer (PCa) microenvironment contains active stromal cells known as 
      cancer-associated fibroblasts (CAF) that may play important roles in influencing 
      tumor progression. Here we studied the role of CAF estrogen receptor alpha (ERalpha) 
      and found that it could protect against PCa invasion. Immunohistochemistry on 
      prostatectomy specimens showed that PCa patients with ERalpha-positive stroma had a 
      significantly lower risk for biochemical recurrence. In vitro invasion assays 
      further confirmed that the stromal ERalpha was able to reduce PCa cell invasion. 
      Dissection of the molecular mechanism revealed that the CAF ERalpha could function 
      through a CAF-epithelial interaction via selectively upregulating thrombospondin 
      2 (Thbs2) and downregulating matrix metalloproteinase 3 (MMP3) at the protein and 
      messenger RNA levels. Chromatin immunoprecipitation assays further showed that 
      ERalpha could bind to an estrogen response element on the promoter of Thbs2. 
      Importantly, knockdown of Thbs2 led to increased MMP3 expression and interruption 
      of the ERalpha mediated invasion suppression, providing further evidence of an 
      ERalpha-Thbs2-MMP3 axis in CAF. In vivo studies using athymic nude mice injected with 
      CWR22Rv1 (22Rv1) PCa epithelial cells and CAF cells +/- ERalpha also confirmed that 
      mice coimplanted with PCa cells and CAF ERalpha+ cells had less tumor foci in the 
      pelvic lymph nodes, less metastases, and tumors showed less angiogenesis, MMP3, 
      and MMP9 (an MMP3 downstream target) positive staining. Together, these data 
      suggest that CAF ERalpha could play protective roles in suppressing PCa metastasis. 
      Our results may lead to developing new and alternative therapeutic approaches to 
      battle PCa via controlling ERalpha signaling in CAF.
CI  - (c) The Author 2013. Published by Oxford University Press. All rights reserved. For 
      Permissions, please email: journals.permissions@oup.com.
FAU - Slavin, Spencer
AU  - Slavin S
AD  - Departments of Urology and Pathology, University of Rochester Medical Center 
      Rochester, 601 Elmwood Avenue, NY 14642, USA.
FAU - Yeh, Chiuan-Ren
AU  - Yeh CR
AD  - Departments of Urology and Pathology, University of Rochester Medical Center 
      Rochester, 601 Elmwood Avenue, NY 14642, USA.
FAU - Da, Jun
AU  - Da J
AD  - Departments of Urology and Pathology, University of Rochester Medical Center 
      Rochester, 601 Elmwood Avenue, NY 14642, USA, Department of Urology, Shanghai 
      Jaotong University, Shanghai, China and.
FAU - Yu, Shengqiang
AU  - Yu S
AD  - Departments of Urology and Pathology, University of Rochester Medical Center 
      Rochester, 601 Elmwood Avenue, NY 14642, USA.
FAU - Miyamoto, Hiroshi
AU  - Miyamoto H
AD  - Departments of Urology and Pathology, University of Rochester Medical Center 
      Rochester, 601 Elmwood Avenue, NY 14642, USA.
FAU - Messing, Edward M
AU  - Messing EM
AD  - Departments of Urology and Pathology, University of Rochester Medical Center 
      Rochester, 601 Elmwood Avenue, NY 14642, USA.
FAU - Guancial, Elizabeth
AU  - Guancial E
AD  - Departments of Hematology and Oncology, University of Rochester Medical Center, 
      Rochester, NY 14642, USA.
FAU - Yeh, Shuyuan
AU  - Yeh S
AD  - Departments of Urology and Pathology, University of Rochester Medical Center 
      Rochester, 601 Elmwood Avenue, NY 14642, USA, Shuyuan_Yeh@urmc.rochester.edu.
LA  - eng
GR  - R01 CA137474/CA/NCI NIH HHS/United States
GR  - CA137474/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20131228
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (Thrombospondins)
RN  - 0 (thrombospondin 2)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - Estrogen Receptor alpha/*metabolism
MH  - Fibroblasts/*metabolism/*pathology
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Knockdown Techniques
MH  - Heterografts
MH  - Humans
MH  - Immunohistochemistry
MH  - Male
MH  - Matrix Metalloproteinase 3/genetics/*metabolism
MH  - Neoplasm Invasiveness
MH  - Phenotype
MH  - Prostatic Neoplasms/genetics/*metabolism/mortality/*pathology
MH  - Protein Binding
MH  - RNA Interference
MH  - Stromal Cells/metabolism/pathology
MH  - Thrombospondins/genetics/*metabolism
PMC - PMC4043239
EDAT- 2014/01/01 06:00
MHDA- 2014/08/05 06:00
PMCR- 2015/06/01
CRDT- 2013/12/31 06:00
PHST- 2013/12/31 06:00 [entrez]
PHST- 2014/01/01 06:00 [pubmed]
PHST- 2014/08/05 06:00 [medline]
PHST- 2015/06/01 00:00 [pmc-release]
AID - bgt488 [pii]
AID - 10.1093/carcin/bgt488 [doi]
PST - ppublish
SO  - Carcinogenesis. 2014 Jun;35(6):1301-9. doi: 10.1093/carcin/bgt488. Epub 2013 Dec 
      28.