Abstract 1441: MYC expression promotes lipid metabolism and metabolic plasticity in human mammary epithelial cell

Jessica C. Casciano, Adam Cohen-Nowak, Johan Vande Voorde, Qifeng Zhang, Susan Chalmers, Mairi Sandison, Ann Hedley, Tony McBryan, Thomas Beer, Hsin-Yao Tang, David W. Speicher, Peter Adams, Xiufeng Liu, Richard Schlegel, John McCarron, Michael J. Wakelam, Eyal Gottlieb, Zachary T. Schug

Research output: Contribution to journalConference Contribution

Abstract

MYC is one of the most commonly mutated and highly amplified oncogenes in human breast cancer. MYC amplifications occur most frequently in triple-negative breast cancers (TNBCs). TNBCs can be divided into two molecular subtypes: basal-like and claudin-low breast cancers. These cancers tend to be extremely aggressive and are strongly associated with disease recurrence, poor prognosis and high mortality. In particular, claudin-low tumors are classified by a loss of tight junctions and cell-to-cell contacts and an enrichment for genes associated with an epithelial-to-mesenchymal transition (EMT) and mammary stem cells (also known as tumor-initiating cells). Despite the high level of disease severity, there are no targeted therapies for claudin-low TNBCs. To address this unmet need, we utilized human mammary epithelial cells (HuMECs) that express oncogenic levels of MYC and a mutant MYC (T58A) to characterize the behavioral and metabolic changes that occur during the formation of MYC-driven breast cancers. We found that MYC regulates the expression of genes associated with cell stemness, EMT, lipid metabolism, and calcium (Ca2+) signaling and that the expression of this gene signature promotes cell growth, survival, migration, and metabolic plasticity. The gene signature of MYC-expressing HuMECs highly correlates with the gene signature of claudin-low breast cancers, therefore highlighting the relevance of our HuMEC model to human claudin-low breast cancer. We found the major drivers underlying the MYC-dependent changes in cell behavior to be stimulation of Ca2+ signaling and strong activation of lipid metabolism. Ca2+ signaling is stimulated through the MYC-dependent repression of Ca2+ efflux mechanisms; elevated cytosolic Ca2+ then consequently stimulates a Ca2+/calmodulin kinase kinase 2 (CAMKK2)/AMPK signaling axis that activates fatty acid scavenging and transport, as well as β-oxidation. Enhanced lipid metabolism thereby provides the necessary biomass (fatty acids) for phospholipid biosynthesis and energy (ATP) to support the metabolically demanding processes of cell growth, proliferation, and migration. In all, our findings provide a strong rationale for targeting lipid metabolism and the Ca2+/CAMKK2/AMPK signaling axis in MYC-driven, and potentially claudin-low, breast cancers.
LanguageEnglish
Number of pages1
JournalCancer Research
Volume78
Issue number13 Suppl
DOIs
Publication statusPublished - 31 Jul 2018

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Lipid Metabolism
Breast
Epithelial Cells
Triple Negative Breast Neoplasms
Breast Neoplasms
Calcium-Calmodulin-Dependent Protein Kinases
Epithelial-Mesenchymal Transition
Fatty Acids
Genes
Calcium Signaling
Neoplastic Stem Cells
Tight Junctions
Growth
Oncogenes
Transcriptome
Biomass
Cell Movement
Neoplasms
Phospholipids
Cell Survival

Keywords

  • MYC
  • triple-negative breast cancers (TNBCs)
  • human mammary epithelial cells (HuMECs)

Cite this

Casciano, Jessica C. ; Cohen-Nowak, Adam ; Vande Voorde, Johan ; Zhang, Qifeng ; Chalmers, Susan ; Sandison, Mairi ; Hedley, Ann ; McBryan, Tony ; Beer, Thomas ; Tang, Hsin-Yao ; Speicher, David W. ; Adams, Peter ; Liu, Xiufeng ; Schlegel, Richard ; McCarron, John ; Wakelam, Michael J. ; Gottlieb, Eyal ; Schug, Zachary T. / Abstract 1441 : MYC expression promotes lipid metabolism and metabolic plasticity in human mammary epithelial cell. In: Cancer Research. 2018 ; Vol. 78, No. 13 Suppl.
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title = "Abstract 1441: MYC expression promotes lipid metabolism and metabolic plasticity in human mammary epithelial cell",
abstract = "MYC is one of the most commonly mutated and highly amplified oncogenes in human breast cancer. MYC amplifications occur most frequently in triple-negative breast cancers (TNBCs). TNBCs can be divided into two molecular subtypes: basal-like and claudin-low breast cancers. These cancers tend to be extremely aggressive and are strongly associated with disease recurrence, poor prognosis and high mortality. In particular, claudin-low tumors are classified by a loss of tight junctions and cell-to-cell contacts and an enrichment for genes associated with an epithelial-to-mesenchymal transition (EMT) and mammary stem cells (also known as tumor-initiating cells). Despite the high level of disease severity, there are no targeted therapies for claudin-low TNBCs. To address this unmet need, we utilized human mammary epithelial cells (HuMECs) that express oncogenic levels of MYC and a mutant MYC (T58A) to characterize the behavioral and metabolic changes that occur during the formation of MYC-driven breast cancers. We found that MYC regulates the expression of genes associated with cell stemness, EMT, lipid metabolism, and calcium (Ca2+) signaling and that the expression of this gene signature promotes cell growth, survival, migration, and metabolic plasticity. The gene signature of MYC-expressing HuMECs highly correlates with the gene signature of claudin-low breast cancers, therefore highlighting the relevance of our HuMEC model to human claudin-low breast cancer. We found the major drivers underlying the MYC-dependent changes in cell behavior to be stimulation of Ca2+ signaling and strong activation of lipid metabolism. Ca2+ signaling is stimulated through the MYC-dependent repression of Ca2+ efflux mechanisms; elevated cytosolic Ca2+ then consequently stimulates a Ca2+/calmodulin kinase kinase 2 (CAMKK2)/AMPK signaling axis that activates fatty acid scavenging and transport, as well as β-oxidation. Enhanced lipid metabolism thereby provides the necessary biomass (fatty acids) for phospholipid biosynthesis and energy (ATP) to support the metabolically demanding processes of cell growth, proliferation, and migration. In all, our findings provide a strong rationale for targeting lipid metabolism and the Ca2+/CAMKK2/AMPK signaling axis in MYC-driven, and potentially claudin-low, breast cancers.",
keywords = "MYC, triple-negative breast cancers (TNBCs), human mammary epithelial cells (HuMECs)",
author = "Casciano, {Jessica C.} and Adam Cohen-Nowak and {Vande Voorde}, Johan and Qifeng Zhang and Susan Chalmers and Mairi Sandison and Ann Hedley and Tony McBryan and Thomas Beer and Hsin-Yao Tang and Speicher, {David W.} and Peter Adams and Xiufeng Liu and Richard Schlegel and John McCarron and Wakelam, {Michael J.} and Eyal Gottlieb and Schug, {Zachary T.}",
year = "2018",
month = "7",
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doi = "10.1158/1538-7445.AM2018-1441",
language = "English",
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journal = "Cancer Research",
issn = "0008-5472",
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Casciano, JC, Cohen-Nowak, A, Vande Voorde, J, Zhang, Q, Chalmers, S, Sandison, M, Hedley, A, McBryan, T, Beer, T, Tang, H-Y, Speicher, DW, Adams, P, Liu, X, Schlegel, R, McCarron, J, Wakelam, MJ, Gottlieb, E & Schug, ZT 2018, 'Abstract 1441: MYC expression promotes lipid metabolism and metabolic plasticity in human mammary epithelial cell' Cancer Research, vol. 78, no. 13 Suppl. https://doi.org/10.1158/1538-7445.AM2018-1441

Abstract 1441 : MYC expression promotes lipid metabolism and metabolic plasticity in human mammary epithelial cell. / Casciano, Jessica C.; Cohen-Nowak, Adam; Vande Voorde, Johan; Zhang, Qifeng; Chalmers, Susan; Sandison, Mairi; Hedley, Ann; McBryan, Tony; Beer, Thomas; Tang, Hsin-Yao; Speicher, David W.; Adams, Peter; Liu, Xiufeng; Schlegel, Richard; McCarron, John; Wakelam, Michael J.; Gottlieb, Eyal; Schug, Zachary T.

In: Cancer Research, Vol. 78, No. 13 Suppl, 31.07.2018.

Research output: Contribution to journalConference Contribution

TY - JOUR

T1 - Abstract 1441

T2 - Cancer Research

AU - Casciano, Jessica C.

AU - Cohen-Nowak, Adam

AU - Vande Voorde, Johan

AU - Zhang, Qifeng

AU - Chalmers, Susan

AU - Sandison, Mairi

AU - Hedley, Ann

AU - McBryan, Tony

AU - Beer, Thomas

AU - Tang, Hsin-Yao

AU - Speicher, David W.

AU - Adams, Peter

AU - Liu, Xiufeng

AU - Schlegel, Richard

AU - McCarron, John

AU - Wakelam, Michael J.

AU - Gottlieb, Eyal

AU - Schug, Zachary T.

PY - 2018/7/31

Y1 - 2018/7/31

N2 - MYC is one of the most commonly mutated and highly amplified oncogenes in human breast cancer. MYC amplifications occur most frequently in triple-negative breast cancers (TNBCs). TNBCs can be divided into two molecular subtypes: basal-like and claudin-low breast cancers. These cancers tend to be extremely aggressive and are strongly associated with disease recurrence, poor prognosis and high mortality. In particular, claudin-low tumors are classified by a loss of tight junctions and cell-to-cell contacts and an enrichment for genes associated with an epithelial-to-mesenchymal transition (EMT) and mammary stem cells (also known as tumor-initiating cells). Despite the high level of disease severity, there are no targeted therapies for claudin-low TNBCs. To address this unmet need, we utilized human mammary epithelial cells (HuMECs) that express oncogenic levels of MYC and a mutant MYC (T58A) to characterize the behavioral and metabolic changes that occur during the formation of MYC-driven breast cancers. We found that MYC regulates the expression of genes associated with cell stemness, EMT, lipid metabolism, and calcium (Ca2+) signaling and that the expression of this gene signature promotes cell growth, survival, migration, and metabolic plasticity. The gene signature of MYC-expressing HuMECs highly correlates with the gene signature of claudin-low breast cancers, therefore highlighting the relevance of our HuMEC model to human claudin-low breast cancer. We found the major drivers underlying the MYC-dependent changes in cell behavior to be stimulation of Ca2+ signaling and strong activation of lipid metabolism. Ca2+ signaling is stimulated through the MYC-dependent repression of Ca2+ efflux mechanisms; elevated cytosolic Ca2+ then consequently stimulates a Ca2+/calmodulin kinase kinase 2 (CAMKK2)/AMPK signaling axis that activates fatty acid scavenging and transport, as well as β-oxidation. Enhanced lipid metabolism thereby provides the necessary biomass (fatty acids) for phospholipid biosynthesis and energy (ATP) to support the metabolically demanding processes of cell growth, proliferation, and migration. In all, our findings provide a strong rationale for targeting lipid metabolism and the Ca2+/CAMKK2/AMPK signaling axis in MYC-driven, and potentially claudin-low, breast cancers.

AB - MYC is one of the most commonly mutated and highly amplified oncogenes in human breast cancer. MYC amplifications occur most frequently in triple-negative breast cancers (TNBCs). TNBCs can be divided into two molecular subtypes: basal-like and claudin-low breast cancers. These cancers tend to be extremely aggressive and are strongly associated with disease recurrence, poor prognosis and high mortality. In particular, claudin-low tumors are classified by a loss of tight junctions and cell-to-cell contacts and an enrichment for genes associated with an epithelial-to-mesenchymal transition (EMT) and mammary stem cells (also known as tumor-initiating cells). Despite the high level of disease severity, there are no targeted therapies for claudin-low TNBCs. To address this unmet need, we utilized human mammary epithelial cells (HuMECs) that express oncogenic levels of MYC and a mutant MYC (T58A) to characterize the behavioral and metabolic changes that occur during the formation of MYC-driven breast cancers. We found that MYC regulates the expression of genes associated with cell stemness, EMT, lipid metabolism, and calcium (Ca2+) signaling and that the expression of this gene signature promotes cell growth, survival, migration, and metabolic plasticity. The gene signature of MYC-expressing HuMECs highly correlates with the gene signature of claudin-low breast cancers, therefore highlighting the relevance of our HuMEC model to human claudin-low breast cancer. We found the major drivers underlying the MYC-dependent changes in cell behavior to be stimulation of Ca2+ signaling and strong activation of lipid metabolism. Ca2+ signaling is stimulated through the MYC-dependent repression of Ca2+ efflux mechanisms; elevated cytosolic Ca2+ then consequently stimulates a Ca2+/calmodulin kinase kinase 2 (CAMKK2)/AMPK signaling axis that activates fatty acid scavenging and transport, as well as β-oxidation. Enhanced lipid metabolism thereby provides the necessary biomass (fatty acids) for phospholipid biosynthesis and energy (ATP) to support the metabolically demanding processes of cell growth, proliferation, and migration. In all, our findings provide a strong rationale for targeting lipid metabolism and the Ca2+/CAMKK2/AMPK signaling axis in MYC-driven, and potentially claudin-low, breast cancers.

KW - MYC

KW - triple-negative breast cancers (TNBCs)

KW - human mammary epithelial cells (HuMECs)

UR - http://cancerres.aacrjournals.org/

U2 - 10.1158/1538-7445.AM2018-1441

DO - 10.1158/1538-7445.AM2018-1441

M3 - Conference Contribution

VL - 78

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 13 Suppl

ER -