PMID- 20395207
OWN - NLM
STAT- MEDLINE
DCOM- 20100428
LR  - 20211020
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 70
IP  - 8
DP  - 2010 Apr 15
TI  - Blockade of CCN6 (WISP3) activates growth factor-independent survival and 
      resistance to anoikis in human mammary epithelial cells.
PG  - 3340-50
LID - 10.1158/0008-5472.CAN-09-4225 [doi]
AB  - CCN6 is a secreted cysteine-rich matricellular protein (36.9 kDa) that exerts 
      growth-inhibitory functions in breast cancer. Reduction or loss of CCN6 protein 
      has been reported in invasive carcinomas of the breast with lymph node metastasis 
      and in inflammatory breast cancer. However, the mechanism by which CCN6 loss 
      promotes breast cancer growth remains to be defined. In the present study, we 
      developed lentiviral-mediated short hairpin RNA CCN6 knockdown (KD) in 
      nontumorigenic mammary epithelial cells MCF10A and HME. We discovered that CCN6 
      KD protects mammary epithelial cells from apoptosis and activates growth 
      factor-independent survival. In the absence of exogenous growth factors, CCN6 KD 
      was able to promote growth under anchorage-independent conditions and triggered 
      resistance to detachment-induced cell death (anoikis). On serum starvation, CCN6 
      KD was sufficient for activation of the phosphatidylinositol 3-kinase (PI3K)/Akt 
      pathway. Growth factor-independent cell survival was stunted in CCN6 KD cells 
      when treated with either human recombinant CCN6 protein or the PI3K inhibitor 
      LY294002. Targeted inhibition of Akt isoforms revealed that the survival 
      advantage rendered by CCN6 KD requires specific activation of Akt-1. The 
      relevance of our studies to human breast cancer is highlighted by the finding 
      that low CCN6 protein levels are associated with upregulated expression of 
      phospho-Akt-1 (Ser(473)) in 21% of invasive breast carcinomas. These results 
      enable us to pinpoint one mechanism by which CCN6 controls survival of breast 
      cells mediated by the PI3K/Akt-1 pathway.
CI  - (c) 2010 AACR.
FAU - Huang, Wei
AU  - Huang W
AD  - Department of Pathology, Comprehensive Cancer Center, University of Michigan 
      Medical School, Ann Arbor, Michigan 48109, USA.
FAU - Gonzalez, Maria E
AU  - Gonzalez ME
FAU - Toy, Kathy A
AU  - Toy KA
FAU - Banerjee, Mousumi
AU  - Banerjee M
FAU - Kleer, Celina G
AU  - Kleer CG
LA  - eng
GR  - R01 CA125577/CA/NCI NIH HHS/United States
GR  - CA125577/CA/NCI NIH HHS/United States
GR  - R01 CA107469/CA/NCI NIH HHS/United States
GR  - R01 CA125577-01A1/CA/NCI NIH HHS/United States
GR  - 5 P30 CA46592/CA/NCI NIH HHS/United States
GR  - K08 CA090876/CA/NCI NIH HHS/United States
GR  - CA107469/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (CCN Intercellular Signaling Proteins)
RN  - 0 (CCN6 protein, human)
RN  - 0 (Chromones)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Insulin-Like Growth Factor Binding Proteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Morpholines)
RN  - 0 (Recombinant Proteins)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
SB  - IM
MH  - *Anoikis
MH  - Apoptosis
MH  - Breast/*metabolism
MH  - CCN Intercellular Signaling Proteins
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Cell Survival
MH  - Chromones/pharmacology
MH  - Enzyme Inhibitors/pharmacology
MH  - Epithelial Cells/*metabolism
MH  - Humans
MH  - Insulin-Like Growth Factor Binding Proteins/*antagonists & inhibitors/chemistry
MH  - Intercellular Signaling Peptides and Proteins/*metabolism
MH  - Morpholines/pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Recombinant Proteins/chemistry
PMC - PMC2856127
MID - NIHMS177796
OTO - NOTNLM
OT  - AKT
OT  - CCN6
OT  - WISP3
OT  - anoikis
OT  - apoptosis
OT  - breast cancer
OT  - growth factor independent
OT  - survival
EDAT- 2010/04/17 06:00
MHDA- 2010/04/29 06:00
PMCR- 2011/04/15
CRDT- 2010/04/17 06:00
PHST- 2010/04/17 06:00 [entrez]
PHST- 2010/04/17 06:00 [pubmed]
PHST- 2010/04/29 06:00 [medline]
PHST- 2011/04/15 00:00 [pmc-release]
AID - 70/8/3340 [pii]
AID - 10.1158/0008-5472.CAN-09-4225 [doi]
PST - ppublish
SO  - Cancer Res. 2010 Apr 15;70(8):3340-50. doi: 10.1158/0008-5472.CAN-09-4225.