PMID- 27746162
OWN - NLM
STAT- MEDLINE
DCOM- 20170731
LR  - 20171116
IS  - 1872-7980 (Electronic)
IS  - 0304-3835 (Linking)
VI  - 384
DP  - 2017 Jan 1
TI  - Diminished DYRK2 sensitizes hormone receptor-positive breast cancer to everolimus
      by the escape from degrading mTOR.
PG  - 27-38
LID - S0304-3835(16)30627-9 [pii]
LID - 10.1016/j.canlet.2016.10.015 [doi]
AB  - Mammalian target of rapamycin (mTOR) inhibitor, everolimus, provides benefit for 
      metastatic hormone receptor positive breast cancer after failure of the endocrine
      therapy. The present report highlights Dual Specificity Tyrosine Phosphorylation 
      Regulated Kinase 2 (DYRK2) as a predictive marker for everolimus sensitivity. The
      key node and KEGG pathway analyses revealed that mTORC1 pathway is activated in
      DYRK2-depleted cells. Everolimus was more effective in DYRK2-depleted cells
      compared with control cells. In xenograft model, everolimus treatment
      significantly inhibited tumor growth compared with vehicle or eribulin treatment.
      In clinical analysis, patients with low DYRK2 expression acquired longer
      treatment period and had higher clinical benefit rate than those with high DYRK2 
      expression (171 vs 82 days; P < 0.05 and 50% vs 12.5%, respectively). We further 
      investigated the underlying mechanism by which DYRK2 regulates mTORC1 pathway.
      The ectopic expression of DYRK2 promoted phosphorylation of Thr631 for the
      ubiquitination and degradation of mTOR. DYRK2 expression levels may thus predict 
      clinical responses to everolimus.
CI  - Copyright (c) 2016 Elsevier Ireland Ltd. All rights reserved.
FAU - Mimoto, Rei
AU  - Mimoto R
AD  - Department of Biochemistry, Jikei University School of Medicine, 3-25-8
      Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan; Department of Surgery, Jikei
      University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461,
      Japan.
FAU - Nihira, Naoe T
AU  - Nihira NT
AD  - Department of Biochemistry, Jikei University School of Medicine, 3-25-8
      Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan; Department of Pathology, Beth 
      Israel Deaconess Medical Center, Harvard Medical School, USA.
FAU - Hirooka, Shinichi
AU  - Hirooka S
AD  - Department of Pathology, Jikei University School of Medicine, 3-25-8
      Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
FAU - Takeyama, Hiroshi
AU  - Takeyama H
AD  - Department of Surgery, Jikei University School of Medicine, 3-25-8
      Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
FAU - Yoshida, Kiyotsugu
AU  - Yoshida K
AD  - Department of Biochemistry, Jikei University School of Medicine, 3-25-8
      Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. Electronic address:
      kyoshida@jikei.ac.jp.
LA  - eng
PT  - Journal Article
DEP - 20161013
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.- (Dyrk kinase)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*therapeutic use
MH  - Breast Neoplasms/*drug therapy/enzymology/pathology
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation
MH  - Everolimus/*therapeutic use
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - MCF-7 Cells
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice, Nude
MH  - Multiprotein Complexes/metabolism
MH  - Mutation
MH  - Phosphorylation
MH  - Proteasome Endopeptidase Complex/metabolism
MH  - Protein Kinase Inhibitors/*therapeutic use
MH  - Protein-Serine-Threonine Kinases/genetics/*metabolism
MH  - Protein-Tyrosine Kinases/genetics/*metabolism
MH  - Proteolysis
MH  - RNA Interference
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/genetics/metabolism
MH  - Time Factors
MH  - Transfection
MH  - Tumor Burden/drug effects
MH  - Ubiquitination
MH  - Xenograft Model Antitumor Assays
OTO - NOTNLM
OT  - *Breast cancer
OT  - *DYRK2
OT  - *Everolimus
OT  - *mTOR pathway
EDAT- 2016/10/28 06:00
MHDA- 2017/08/02 06:00
CRDT- 2016/11/07 06:00
PHST- 2016/07/11 00:00 [received]
PHST- 2016/10/04 00:00 [revised]
PHST- 2016/10/04 00:00 [accepted]
PHST- 2016/10/28 06:00 [pubmed]
PHST- 2017/08/02 06:00 [medline]
PHST- 2016/11/07 06:00 [entrez]
AID - S0304-3835(16)30627-9 [pii]
AID - 10.1016/j.canlet.2016.10.015 [doi]
PST - ppublish
SO  - Cancer Lett. 2017 Jan 1;384:27-38. doi: 10.1016/j.canlet.2016.10.015. Epub 2016
      Oct 13.