The enhancing effects of obesity on mammary tumor growth and Akt/mTOR pathway activation persist after weight loss and are reversed by RAD001

Mol Carcinog. 2013 Jun;52(6):446-58. doi: 10.1002/mc.21878. Epub 2012 Jan 30.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Diet
  • Everolimus
  • Female
  • Hormones / blood
  • Insulin-Like Growth Factor I / metabolism
  • Mammary Glands, Animal / drug effects
  • Mammary Glands, Animal / metabolism
  • Mammary Glands, Animal / pathology
  • Mammary Neoplasms, Experimental / complications*
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Obesity / complications*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects
  • Sirolimus / analogs & derivatives*
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases / metabolism*
  • Weight Loss / drug effects
  • Wnt1 Protein / metabolism

Substances

  • Antineoplastic Agents
  • Hormones
  • Wnt1 Protein
  • Wnt1 protein, mouse
  • Insulin-Like Growth Factor I
  • Everolimus
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Sirolimus