PMID- 22037215
OWN - NLM
STAT- MEDLINE
DCOM- 20120913
LR  - 20220410
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 31
IP  - 27
DP  - 2012 Jul 5
TI  - Inhibiting PI3K reduces mammary tumor growth and induces hyperglycemia in a mouse 
      model of insulin resistance and hyperinsulinemia.
PG  - 3213-22
LID - 10.1038/onc.2011.495 [doi]
AB  - Women with type 2 diabetes mellitus (T2DM) are at a greater risk of developing 
      and dying from breast cancer than women without T2DM. Insulin resistance and 
      hyperinsulinemia underlie the pathogenesis of T2DM. In the MKR mouse model of 
      insulin resistance, we have previously shown increased activation of the 
      phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway in association with 
      accelerated mammary tumor growth. In this study, we demonstrate that inhibiting 
      PI3K with the oral pan-class I PI3K inhibitor, NVP-BKM120 reduced the growth of 
      Met-1 and MCNeuA mammary tumor orthografts in the MKR mouse. NVP-BKM120 treatment 
      decreased phosphorylation of Akt and S6 ribosomal protein (S6rp); no change in 
      Erk1/2 phosphorylation was seen. Hyperglycemia, hypertriglyceridemia and greater 
      hyperinsulinemia developed in the MKR mice treated with NVP-BKM120. We previously 
      reported reduced tumor growth using intraperitoneal rapamycin in the MKR mouse, 
      with the development of hyperglycemia and hypertriglyceridemia. Therefore, we 
      examined whether the oral PI3K/mTOR inhibitor NVP-BEZ235 augmented the tumor 
      suppressing effects of PI3K inhibition. We also investigated the effect of 
      targeted PI3K/mTOR inhibition on PI3K/Akt/mTOR and Erk1/2 signaling, and the 
      potential effects on glycemia. NVP-BEZ235 suppressed the growth of Met-1 and 
      MCNeuA tumor orthografts, and decreased Akt and S6rp phosphorylation, despite 
      increased Erk1/2 phosphorylation in Met-1 orthografts of MKR mice. Less marked 
      hyperglycemia and hyperinsulinemia developed with NVP-BEZ235 than NVP-BKM120. 
      Overall, the results of this study demonstrated that inhibiting PI3K/Akt/mTOR 
      signaling with the oral agents NVP-BKM120 and NVP-BEZ235 decreased mammary tumor 
      growth in the hyperinsulinemic MKR mouse. Inhibiting PI3K alone led to more 
      severe metabolic derangement than inhibiting both PI3K and mTOR. Therefore, PI3K 
      may be an important target for the treatment of breast cancer in women with 
      insulin resistance. Monitoring for hyperglycemia and dyslipidemia should be 
      considered when using these agents in humans, given the metabolic changes 
      detected in this study.
FAU - Gallagher, E J
AU  - Gallagher EJ
AD  - Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of 
      Medicine, New York, NY 10029, USA.
FAU - Fierz, Y
AU  - Fierz Y
FAU - Vijayakumar, A
AU  - Vijayakumar A
FAU - Haddad, N
AU  - Haddad N
FAU - Yakar, S
AU  - Yakar S
FAU - LeRoith, D
AU  - LeRoith D
LA  - eng
GR  - R01 CA128799/CA/NCI NIH HHS/United States
GR  - R01 CA128799-01A1/CA/NCI NIH HHS/United States
GR  - R01-5R01-CA128799/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111031
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Imidazoles)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - RUJ6Z9Y0DT (dactolisib)
SB  - IM
MH  - Animals
MH  - Cell Proliferation/drug effects
MH  - Cell Transformation, Neoplastic
MH  - Disease Progression
MH  - Drug Interactions
MH  - Female
MH  - Humans
MH  - Hyperglycemia/*chemically induced
MH  - Hyperinsulinism/*complications
MH  - Imidazoles/adverse effects/pharmacology/therapeutic use
MH  - *Insulin Resistance
MH  - Mammary Neoplasms, Experimental/complications/*drug therapy/metabolism/*pathology
MH  - Mice
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - Protein Kinase Inhibitors/adverse effects/*pharmacology/therapeutic use
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Quinolines/adverse effects/pharmacology/therapeutic use
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
PMC - PMC3275680
MID - NIHMS328215
EDAT- 2011/11/01 06:00
MHDA- 2012/09/14 06:00
PMCR- 2013/01/05
CRDT- 2011/11/01 06:00
PHST- 2011/11/01 06:00 [entrez]
PHST- 2011/11/01 06:00 [pubmed]
PHST- 2012/09/14 06:00 [medline]
PHST- 2013/01/05 00:00 [pmc-release]
AID - onc2011495 [pii]
AID - 10.1038/onc.2011.495 [doi]
PST - ppublish
SO  - Oncogene. 2012 Jul 5;31(27):3213-22. doi: 10.1038/onc.2011.495. Epub 2011 Oct 31.