PMID- 22290600
OWN - NLM
STAT- MEDLINE
DCOM- 20130617
LR  - 20211203
IS  - 1098-2744 (Electronic)
IS  - 0899-1987 (Linking)
VI  - 52
IP  - 6
DP  - 2013 Jun
TI  - The enhancing effects of obesity on mammary tumor growth and Akt/mTOR pathway 
      activation persist after weight loss and are reversed by RAD001.
PG  - 446-58
LID - 10.1002/mc.21878 [doi]
AB  - The prevalence of obesity, an established risk and progression factor for 
      postmenopausal breast cancer, remains high in US women. Activation of 
      Akt/mammalian target of rapamycin (mTOR) signaling plays a key role in the 
      obesity-breast cancer link. However, the impact of weight normalization in obese 
      postmenopausal women on breast tumorigenesis and/or Akt/mTOR activation is poorly 
      characterized. To model this, ovariectomized female C57BL/6 mice were fed a 
      control diet (n = 20), a calorie restriction (CR) regimen (n = 20), or a 
      diet-induced obesity (DIO) diet (n = 30). At week 17, DIO mice were switched to 
      control diet, resulting in formerly obese (FOb) mice with weights identical to 
      the controls by week 20. MMTV-Wnt-1 mammary tumor cells were injected at 20 wk 
      into each mouse. Two weeks post-injection, vehicle or the mTOR inhibitor RAD001 
      at 10 or 15 mg/kg body weight (n = 10/diet group) was administered by gavage 
      twice/week until termination. Relative to controls, CR mice had decreased (and 
      DIO mice had increased) serum insulin-like growth factor-1 (IGF-1) and 
      phosphorylation of Akt/mTOR pathway components. RAD001 decreased tumor growth in 
      the CR, control, and FOb mice. Wnt-1 tumor cells treated in vitro with serum from 
      mice from each group established that diet-dependent circulating factors 
      contribute to tumor growth and invasiveness. These findings suggest weight 
      normalization in obese mice does not immediately reverse tumor progression or 
      Akt/mTOR activation. Treatment with RAD001 blocked mammary tumor development and 
      mTOR activation observed in the FOb mice, suggesting combination of lifestyle and 
      pharmacologic strategies may be effective for breaking the obesity-breast cancer 
      link.
CI  - Copyright (c) 2012 Wiley Periodicals, Inc.
FAU - De Angel, Rebecca E
AU  - De Angel RE
AD  - Department of Nutritional Sciences, University of Texas at Austin, Austin, TX 
      78712, USA.
FAU - Conti, Claudio J
AU  - Conti CJ
FAU - Wheatley, Karrie E
AU  - Wheatley KE
FAU - Brenner, Andrew J
AU  - Brenner AJ
FAU - Otto, Glen
AU  - Otto G
FAU - Degraffenried, Linda A
AU  - Degraffenried LA
FAU - Hursting, Stephen D
AU  - Hursting SD
LA  - eng
GR  - F31CA139954/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20120130
PL  - United States
TA  - Mol Carcinog
JT  - Molecular carcinogenesis
JID - 8811105
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Hormones)
RN  - 0 (Wnt1 Protein)
RN  - 0 (Wnt1 protein, mouse)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*therapeutic use
MH  - Cell Line, Tumor
MH  - Diet
MH  - Everolimus
MH  - Female
MH  - Hormones/blood
MH  - Insulin-Like Growth Factor I/metabolism
MH  - Mammary Glands, Animal/drug effects/metabolism/pathology
MH  - Mammary Neoplasms, Experimental/*complications/*drug therapy/metabolism/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Obese
MH  - Obesity/*complications
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*analogs & derivatives/therapeutic use
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Weight Loss/drug effects
MH  - Wnt1 Protein/metabolism
EDAT- 2012/02/01 06:00
MHDA- 2013/06/19 06:00
CRDT- 2012/02/01 06:00
PHST- 2011/12/21 00:00 [received]
PHST- 2012/01/03 00:00 [accepted]
PHST- 2012/02/01 06:00 [entrez]
PHST- 2012/02/01 06:00 [pubmed]
PHST- 2013/06/19 06:00 [medline]
AID - 10.1002/mc.21878 [doi]
PST - ppublish
SO  - Mol Carcinog. 2013 Jun;52(6):446-58. doi: 10.1002/mc.21878. Epub 2012 Jan 30.