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

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

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1
Affiliations of authors: University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX (GV-T, LPh, FZ, P-CC, J-HS, HHC, CG, CC, FJE, M-HL, S-CJY); Cancer Biology Graduate Program (GV-T, P-CC, J-HS, HHC, CC, M-HL), Genes and Development Graduate Program (CG, M-HL); Department of Molecular and Cellular Oncology (EF-M, GV-T, LPh, FZ, P-CC, J-HS, HHC, RZ, JC, CG, CC, FJE, M-HL), Department of Breast Medical Oncology (FJE, GNH, LPu); Department of Biostatistics (JE), Department of Bioinformatics and Computational Biology (YQ); Department of Pathology (YZ, YW, WFS); Department of Emergency Medicine (J-SC, S-CJY), and Department of Endocrine Neoplasia and Hormonal Disorders (S-CJY), The University of Texas MD Anderson Cancer Center, Houston, TX; Center for Cancer & Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX (YL, WLM); Present address: Breast Cancer Program, Yale Cancer Center, New Haven, CT (LPu).
2
Affiliations of authors: University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX (GV-T, LPh, FZ, P-CC, J-HS, HHC, CG, CC, FJE, M-HL, S-CJY); Cancer Biology Graduate Program (GV-T, P-CC, J-HS, HHC, CC, M-HL), Genes and Development Graduate Program (CG, M-HL); Department of Molecular and Cellular Oncology (EF-M, GV-T, LPh, FZ, P-CC, J-HS, HHC, RZ, JC, CG, CC, FJE, M-HL), Department of Breast Medical Oncology (FJE, GNH, LPu); Department of Biostatistics (JE), Department of Bioinformatics and Computational Biology (YQ); Department of Pathology (YZ, YW, WFS); Department of Emergency Medicine (J-SC, S-CJY), and Department of Endocrine Neoplasia and Hormonal Disorders (S-CJY), The University of Texas MD Anderson Cancer Center, Houston, TX; Center for Cancer & Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX (YL, WLM); Present address: Breast Cancer Program, Yale Cancer Center, New Haven, CT (LPu). syeung@mdanderson.org mhlee@mdanderson.org.

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.

PMID:
24957076
PMCID:
PMC4110474
DOI:
10.1093/jnci/dju158
[Indexed for MEDLINE]
Free PMC Article

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