PMID- 17545609
OWN - NLM
STAT- MEDLINE
DCOM- 20070726
LR  - 20171116
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 11
DP  - 2007 Jun 1
TI  - Metastatic potential of 21T human breast cancer cells depends on Akt/protein 
      kinase B activation.
PG  - 5293-9
AB  - Most cancer lethality is caused by metastasis. To gain insight into the molecular 
      basis of tumor progression to metastasis, we used the 21T series of human mammary 
      epithelial cells obtained by successive biopsies from one breast cancer patient. 
      The c-erbB2 gene is amplified and overexpressed in each of three 21T tumor lines. 
      The erbB receptor tyrosine kinase-activated phosphatidylinositol 3-kinase/Akt 
      signaling cascade is crucial for the development and maintenance of epithelial 
      cells, and dysregulation of this pathway is frequently associated with cellular 
      transformation and cancer. For Akt to be fully activated, Ser(473) on its COOH 
      terminus needs to be phosphorylated. We detected more Ser(473) Akt 
      phosphorylation in MT cells, derived from a pleural effusion, compared with cells 
      from the primary tumor. This phosphorylation has recently been shown to be 
      catalyzed by mammalian target of rapamycin (mTOR)/rictor kinase. By using genetic 
      and pharmacologic activators and inhibitors, we showed that Ser(473) Akt 
      phosphorylation is more sensitive to mTOR/rictor inhibition in metastatic tumor 
      cells than normal mammary epithelial and primary tumor cells. The mTOR/rictor 
      kinase activity was indispensable for both Ser(473) Akt phosphorylation and 
      migration of metastatic MT2 cells. In addition, a large decrease of protein 
      phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP) was found, 
      which could be responsible for the overexpression of Ser(473) Akt in MT cells. 
      Our data indicate that these breast cancer cells acquire new vulnerabilities, 
      rictor and PHLPP, which might provide an Achilles' heel for therapeutic 
      intervention of breast cancer metastasis.
FAU - Qiao, Meng
AU  - Qiao M
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical 
      School, Boston, Massachusetts 02135, USA. meng_qiao@dfci.harvard.edu
FAU - Iglehart, J Dirk
AU  - Iglehart JD
FAU - Pardee, Arthur B
AU  - Pardee AB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Carrier Proteins)
RN  - 0 (Neuregulin-1)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RICTOR protein, human)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.1.3.16 (PHLPP1 protein, human)
RN  - EC 3.1.3.16 (Phosphoprotein Phosphatases)
SB  - IM
MH  - Breast Neoplasms/*enzymology/*pathology
MH  - Carcinoma, Ductal, Breast/enzymology/pathology
MH  - Carrier Proteins/metabolism
MH  - Cell Line, Tumor
MH  - Enzyme Activation
MH  - Female
MH  - Humans
MH  - Neoplasm Metastasis
MH  - Neuregulin-1
MH  - Nuclear Proteins/biosynthesis/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoprotein Phosphatases/biosynthesis/metabolism
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Rapamycin-Insensitive Companion of mTOR Protein
MH  - Receptor, ErbB-2/metabolism
EDAT- 2007/06/05 09:00
MHDA- 2007/07/27 09:00
CRDT- 2007/06/05 09:00
PHST- 2007/06/05 09:00 [pubmed]
PHST- 2007/07/27 09:00 [medline]
PHST- 2007/06/05 09:00 [entrez]
AID - 67/11/5293 [pii]
AID - 10.1158/0008-5472.CAN-07-0877 [doi]
PST - ppublish
SO  - Cancer Res. 2007 Jun 1;67(11):5293-9. doi: 10.1158/0008-5472.CAN-07-0877.