Effects of obesity on transcriptomic changes and cancer hallmarks in estrogen receptor-positive breast cancer

J Natl Cancer Inst. 2014 Jun 23;106(7):dju158. doi: 10.1093/jnci/dju158. Print 2014 Jul.

Abstract

Background: Obesity increases the risk of cancer death among postmenopausal women with estrogen receptor-positive (ER+) breast cancer, but the direct evidence for the mechanisms is lacking. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating this epidemiologic phenomenon.

Methods: We analyzed transcriptomic profiles of pretreatment biopsies from a prospective cohort of 137 ER+ breast cancer patients. We generated transgenic (MMTV-TGFα;A (y) /a) and orthotopic/syngeneic (A (y) /a) obese mouse models to investigate the effect of obesity on tumorigenesis and tumor progression and to determine biological mechanisms using whole-genome transcriptome microarrays and protein analyses. We used a coculture system to examine the impact of adipocytes/adipokines on breast cancer cell proliferation. All statistical tests were two-sided.

Results: Functional transcriptomic analysis of patients revealed the association of obesity with 59 biological functional changes (P < .05) linked to cancer hallmarks. Gene enrichment analysis revealed enrichment of AKT-target genes (P = .04) and epithelial-mesenchymal transition genes (P = .03) in patients. Our obese mouse models demonstrated activation of the AKT/mTOR pathway in obesity-accelerated mammary tumor growth (3.7- to 7.0-fold; P < .001; n = 6-7 mice per group). Metformin or everolimus can suppress obesity-induced secretion of adipokines and breast tumor formation and growth (0.5-fold, P = .04; 0.3-fold, P < .001, respectively; n = 6-8 mice per group). The coculture model revealed that adipocyte-secreted adipokines (eg, TIMP-1) regulate adipocyte-induced breast cancer cell proliferation and invasion. Metformin suppress adipocyte-induced cell proliferation and adipocyte-secreted adipokines in vitro.

Conclusions: Adipokine secretion and AKT/mTOR activation play important roles in obesity-accelerated breast cancer aggressiveness in addition to hyperinsulinemia, estrogen signaling, and inflammation. Metformin and everolimus have potential for therapeutic interventions of ER+ breast cancer patients with obesity.

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

  • Adipocytes
  • Adipokines / metabolism
  • Aged
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Biomarkers, Tumor / metabolism*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / etiology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Everolimus
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Metformin / pharmacology*
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Obesity / complications*
  • Obesity / epidemiology
  • Obesity / genetics
  • Obesity / metabolism*
  • Postmenopause
  • Prospective Studies
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Estrogen / metabolism*
  • Signal Transduction
  • Sirolimus / analogs & derivatives*
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / metabolism
  • Transcriptome*

Substances

  • Adipokines
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Receptors, Estrogen
  • Metformin
  • Everolimus
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Sirolimus