TY - JOUR
T1 - Effects of obesity on transcriptomic changes and cancer hallmarks in estrogen receptor-positive breast cancer
AU - Fuentes-Mattei, Enrique
AU - Velazquez-Torres, Guermarie
AU - Phan, Liem
AU - Zhang, Fanmao
AU - Chou, Ping Chieh
AU - Shin, Ji Hyun
AU - Choi, Hyun Ho
AU - Chen, Jiun Sheng
AU - Zhao, Ruiying
AU - Chen, Jian
AU - Gully, Chris
AU - Carlock, Colin
AU - Qi, Yuan
AU - Zhang, Ya
AU - Wu, Yun
AU - Esteva, Francisco J.
AU - Luo, Yongde
AU - McKeehan, Wallace L.
AU - Ensor, Joe
AU - Hortobagyi, Gabriel N.
AU - Pusztai, Lajos
AU - Fraser Symmans, W.
AU - Lee, Mong Hong
AU - Jim Yeung, Sai Ching
N1 - Funding Information:
This work was supported by a Susan G. Komen for the Cure Promise Grant (KG081048 to SCY, MHL, FJE, and WLM); and the National Cancer Institute at the National Institutes of Health (RO1-CA089266 to MHL; Cancer Center Support Grant P30-CA16672 to The University of Texas MD Anderson Cancer Center).FJE and LPu were supported by the Breast Cancer Research Foundation. EFM was supported by the National Cancer Institute at the National Institutes of Health Training Grant Program in Molecular Genetics (T32-CA009299) and National Institutes of Health Loan Repayment Program. GVT was supported by a National Institutes of Health cancer prevention fellowship (R25T CA57730) and then by a National Institutes of Health minority supplement (3-R01CA089266-08S1, 3-R01CA089266-09S1, and 3-R01CA089266-10S1; PI: MHL). LPh was supported by the Vietnam Education Foundation, the Rosalie B. Hite Foundation, and the Department of Defense Breast Cancer Research Program (W81XWH-10–0171).
PY - 2014/7/9
Y1 - 2014/7/9
N2 - 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.
AB - 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.
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U2 - 10.1093/jnci/dju158
DO - 10.1093/jnci/dju158
M3 - Article
C2 - 24957076
AN - SCOPUS:84905261317
SN - 0027-8874
VL - 106
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 7
M1 - dju158
ER -