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Cancer Res. 2019 May 15;79(10):2494-2510. doi: 10.1158/0008-5472.CAN-18-2849. Epub 2019 Mar 12.

Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling.

Author information

1
Department of Food Sciences and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, Illinois. zmadake2@illinois.edu.
2
Division of Nutritional Sciences, University of Illinois, Urbana-Champaign, Urbana, Illinois.
3
National Center for Supercomputing Applications, University of Illinois, Urbana-Champaign, Urbana, Illinois.
4
Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Urbana, Illinois.
5
Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois.
6
Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, Illinois.
7
Department of Food Sciences and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, Illinois.
8
Department of Pathobiology, University of Illinois, Urbana-Champaign, Urbana, Illinois.
9
Department of Chemistry, University of Illinois, Urbana-Champaign, Urbana, Illinois.
10
Susan G. Komen Tissue Bank at the IU Simon Cancer Center, Indianapolis, Indiana.
11
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
12
Department of Comparative Biosciences, University of Illinois, Urbana-Champaign, Urbana, Illinois.

Abstract

Obesity is a risk factor for postmenopausal estrogen receptor alpha (ERα)-positive (ER+) breast cancer. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERα signaling have yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in plasma samples from women at high risk for breast cancer, which led us to focus on factors that were differentially present in plasma of obese versus nonobese postmenopausal women. These studies, combined with in vitro assays, identified free fatty acids (FFA) as circulating plasma factors that correlated with increased proliferation and aggressiveness in ER+ breast cancer cells. FFAs activated both the ERα and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which targets ERα and mTOR signaling, was able to block changes induced by FFA and was more effective in the presence of FFA. Collectively, these data suggest a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ER+ breast cancer in postmenopausal women. Furthermore, they provide a basis for preclinical and clinical trials where the impact of agents that target ERα and mTOR signaling cross-talk would be tested to prevent ER+ breast cancers in obese postmenopausal women. SIGNIFICANCE: These findings show that obesity-associated changes in certain blood metabolites rewire metabolic programs in cancer cells, influence mammary epithelial cell tumorigenicity and aggressiveness, and increase breast cancer risk.

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