Free fatty acids rewire cancer metabolism in obesity-associated breast cancer via estrogen receptor and mTOR signaling

Zeynep Madak-Erdogan, Shoham Band, Yiru C. Zhao, Brandi P. Smith, Eylem Kulkoyluoglu-Cotul, Qianying Zuo, Ashlie Santaliz Casiano, Kinga Wrobel, Gianluigi Rossi, Rebecca L. Smith, Sung Hoon Kim, John A. Katzenellenbogen, Mariah L. Johnson, Meera Patel, Natascia Marino, Anna Maria Storniolo, Jodi A. Flaws11

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)2494-2510
Number of pages17
JournalCancer Research
Volume79
Issue number10
DOIs
StatePublished - Jan 1 2019

Fingerprint

Estrogen Receptor alpha
Nonesterified Fatty Acids
Estrogen Receptors
Obesity
Breast Neoplasms
Neoplasms
Estrogens
Breast
Epithelial Cells
Clinical Trials

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Madak-Erdogan, Z., Band, S., Zhao, Y. C., Smith, B. P., Kulkoyluoglu-Cotul, E., Zuo, Q., ... Flaws11, J. A. (2019). Free fatty acids rewire cancer metabolism in obesity-associated breast cancer via estrogen receptor and mTOR signaling. Cancer Research, 79(10), 2494-2510. https://doi.org/10.1158/0008-5472.CAN-18-2849

Free fatty acids rewire cancer metabolism in obesity-associated breast cancer via estrogen receptor and mTOR signaling. / Madak-Erdogan, Zeynep; Band, Shoham; Zhao, Yiru C.; Smith, Brandi P.; Kulkoyluoglu-Cotul, Eylem; Zuo, Qianying; Casiano, Ashlie Santaliz; Wrobel, Kinga; Rossi, Gianluigi; Smith, Rebecca L.; Kim, Sung Hoon; Katzenellenbogen, John A.; Johnson, Mariah L.; Patel, Meera; Marino, Natascia; Storniolo, Anna Maria; Flaws11, Jodi A.

In: Cancer Research, Vol. 79, No. 10, 01.01.2019, p. 2494-2510.

Research output: Contribution to journalArticle

Madak-Erdogan, Z, Band, S, Zhao, YC, Smith, BP, Kulkoyluoglu-Cotul, E, Zuo, Q, Casiano, AS, Wrobel, K, Rossi, G, Smith, RL, Kim, SH, Katzenellenbogen, JA, Johnson, ML, Patel, M, Marino, N, Storniolo, AM & Flaws11, JA 2019, 'Free fatty acids rewire cancer metabolism in obesity-associated breast cancer via estrogen receptor and mTOR signaling', Cancer Research, vol. 79, no. 10, pp. 2494-2510. https://doi.org/10.1158/0008-5472.CAN-18-2849
Madak-Erdogan, Zeynep ; Band, Shoham ; Zhao, Yiru C. ; Smith, Brandi P. ; Kulkoyluoglu-Cotul, Eylem ; Zuo, Qianying ; Casiano, Ashlie Santaliz ; Wrobel, Kinga ; Rossi, Gianluigi ; Smith, Rebecca L. ; Kim, Sung Hoon ; Katzenellenbogen, John A. ; Johnson, Mariah L. ; Patel, Meera ; Marino, Natascia ; Storniolo, Anna Maria ; Flaws11, Jodi A. / Free fatty acids rewire cancer metabolism in obesity-associated breast cancer via estrogen receptor and mTOR signaling. In: Cancer Research. 2019 ; Vol. 79, No. 10. pp. 2494-2510.
@article{678c5d201928440394edf86f11772823,
title = "Free fatty acids rewire cancer metabolism in obesity-associated breast cancer via estrogen receptor and mTOR signaling",
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 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.",
author = "Zeynep Madak-Erdogan and Shoham Band and Zhao, {Yiru C.} and Smith, {Brandi P.} and Eylem Kulkoyluoglu-Cotul and Qianying Zuo and Casiano, {Ashlie Santaliz} and Kinga Wrobel and Gianluigi Rossi and Smith, {Rebecca L.} and Kim, {Sung Hoon} and Katzenellenbogen, {John A.} and Johnson, {Mariah L.} and Meera Patel and Natascia Marino and Storniolo, {Anna Maria} and Flaws11, {Jodi A.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1158/0008-5472.CAN-18-2849",
language = "English (US)",
volume = "79",
pages = "2494--2510",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

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

AU - Flaws11, Jodi A.

PY - 2019/1/1

Y1 - 2019/1/1

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.

UR - http://www.scopus.com/inward/record.url?scp=85066038960&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066038960&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-18-2849

DO - 10.1158/0008-5472.CAN-18-2849

M3 - Article

C2 - 30862719

AN - SCOPUS:85066038960

VL - 79

SP - 2494

EP - 2510

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 10

ER -