ONCOmmunity

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

By: Enrique Fuentes-Mattei, Guermarie Velazquez-Torres, Liem Phan, Fanmao Zhang, Ping-Chieh Chou, Ji-Hyun Shin, Hyun Ho Choi, Jiun-Sheng Chen, Ruiying Zhao, Jian Chen, Chris Gully, Colin Carlock, Yuan Qi, Ya Zhang, Yun Wu, Francisco J Esteva, Yongde Luo, Wallace L McKeehan, Joe Ensor, Gabriel N Hortobagyi, Lajos Pusztai, W Fraser Symmans, Mong-Hong Lee, Sai-Ching Jim Yeung

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).
2014-7-; doi: 10.1093/jnci/dju158

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.