Journal
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
Volume 106, Issue 7, Pages -Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/dju158
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Funding
- Susan G. Komen for the Cure Promise Grant [KG081048]
- National Cancer Institute at the National Institutes of Health (Cancer Center Support Grant) [RO1-CA089266, P30-CA16672]
- Breast Cancer Research Foundation
- National Cancer Institute at the National Institutes of Health Training Grant Program in Molecular Genetics [T32-CA009299]
- National Institutes of Health Loan Repayment Program
- National Institutes of Health cancer prevention fellowship [R25T CA57730]
- National Institutes of Health minority supplement [3-R01CA089266-08S1, 3-R01CA089266-09S1, 3-R01CA089266-10S1]
- Vietnam Education Foundation
- Rosalie B. Hite Foundation
- Department of Defense Breast Cancer Research Program [W81XWH-10-0171]
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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-TGF alpha;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.
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