TY - JOUR
T1 - Free fatty acids rewire cancer metabolism in obesity-associated breast cancer via estrogen receptor and mTOR signaling
AU - Madak-Erdogan, Zeynep
AU - Band, Shoham
AU - Zhao, Yiru C.
AU - Smith, Brandi P.
AU - Kulkoyluoglu-Cotul, Eylem
AU - Zuo, Qianying
AU - Casiano, Ashlie Santaliz
AU - Wrobel, Kinga
AU - Rossi, Gianluigi
AU - Smith, Rebecca L.
AU - Kim, Sung Hoon
AU - Katzenellenbogen, John A.
AU - Johnson, Mariah L.
AU - Patel, Meera
AU - Marino, Natascia
AU - Storniolo, Anna Maria V.
AU - Flaws11, Jodi A.
N1 - Funding Information:
This work was supported by grants from the University of Illinois, Office of the Vice Chancellor for Research, College of ACES FIRE grant (to Z. Madak-Erdogan) and the National Institute of Food and Agriculture, U.S. Department of Agriculture, award ILLU-698-909 (to Z. Madak-Erdogan). We would like to thank to Dr. Alvaro Hernandez, Dr. Mark Band, and Dr. Chris Wright for assistance with RNASeq experiments. We would like to thank Dr. Gokhan Hotamisligil for his critical reading of our manuscript.
Funding Information:
Z. Madak-Erdogan reports receiving a commercial research grant from Pfizer and other commercial research support from Corteva Agrisciences. Z. Madak-Erdogan, J.A. Katzenellenbogen, and S.H. Kim are coinventors on several patents entitled "Novel Compounds Which Activate Estrogen Receptors and Compositions and Methods of Using the Same," which include protection of PaPE-1. Z. Madak-Erdogan was a principal investigator on an investigator-initiated grant from Corteva Agrisciences. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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 andmTORsignaling 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.
AB - 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 andmTORsignaling 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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U2 - 10.1158/0008-5472.CAN-18-2849
DO - 10.1158/0008-5472.CAN-18-2849
M3 - Article
C2 - 30862719
AN - SCOPUS:85066038960
SN - 0008-5472
VL - 79
SP - 2494
EP - 2510
JO - Cancer Research
JF - Cancer Research
IS - 10
ER -