MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer

Casciano, Jessica C.; Perry, Caroline; Cohen‐Nowak, Adam; Miller, Katelyn D.; Voorde, Johan Vande; Zhang, Qifeng; Chalmers, Susan; Sandison, Mairi E.; Liu, Qin; Hedley, Ann; McBryan, Tony; Tang, Hsin‐Yao; Gorman, Nicole; Beer, T. M.; Speicher, David W.; Adams, Peter D.; Li, Xuefeng; Schlegel, Richard; McCarron, John G.; Wakelam, Michael J.O.; Gottlieb, Eyal; Kossenkov, Andrew V.; Schug, Zachary T.

doi:10.1038/s41416-019-0711-3

Cited by 59 publications

(53 citation statements)

References 86 publications

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“… 62 Similar to neuroblastoma, in FL5.12 pre-B cells and MYC-driven triple-negative breast cancer cells, MYC also promotes FAO. 63 – 65 In human mammary epithelial cells that express oncogenic levels of MYC, MYC promotes both CD36 expression at the plasma membrane and CPT1A/CPT2 expression at inner mitochondrial membrane to take up fatty acids that are destined for oxidation in the mitochondria. 65 Moreover, MYC alters calcium (Ca 2+ ) signaling and then promotes FAO by activating a Ca 2+ -CAMKK2-AMP-activated kinase (AMPK) axis.…”

Section: Myc Regulation Of Lipid Metabolismmentioning

confidence: 99%

“… 63 – 65 In human mammary epithelial cells that express oncogenic levels of MYC, MYC promotes both CD36 expression at the plasma membrane and CPT1A/CPT2 expression at inner mitochondrial membrane to take up fatty acids that are destined for oxidation in the mitochondria. 65 Moreover, MYC alters calcium (Ca 2+ ) signaling and then promotes FAO by activating a Ca 2+ -CAMKK2-AMP-activated kinase (AMPK) axis. 65 In contrast, in rat fibroblasts, MYC suppresses FAO by downregulating the similar series of critical enzymes, such as HADHA, HADHB, ACADL (acyl-CoA dehydrogenase, long-chain), and ACADVL (acyl-CoA dehydrogenase, very long-chain).…”

Section: Myc Regulation Of Lipid Metabolismmentioning

confidence: 99%

“… 65 Moreover, MYC alters calcium (Ca 2+ ) signaling and then promotes FAO by activating a Ca 2+ -CAMKK2-AMP-activated kinase (AMPK) axis. 65 In contrast, in rat fibroblasts, MYC suppresses FAO by downregulating the similar series of critical enzymes, such as HADHA, HADHB, ACADL (acyl-CoA dehydrogenase, long-chain), and ACADVL (acyl-CoA dehydrogenase, very long-chain). 33 Most likely, whether MYC promotes or suppresses FAO is a cell context-dependent event.…”

Section: Myc Regulation Of Lipid Metabolismmentioning

confidence: 99%

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Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat

Dong

Liu

et al. 2020

Sig Transduct Target Ther

193

169

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Cancer cells must rewire cellular metabolism to satisfy the demands of unbridled growth and proliferation. As such, most human cancers differ from normal counterpart tissues by a plethora of energetic and metabolic reprogramming. Transcription factors of the MYC family are deregulated in up to 70% of all human cancers through a variety of mechanisms. Oncogenic levels of MYC regulates almost every aspect of cellular metabolism, a recently revisited hallmark of cancer development. Meanwhile, unrestrained growth in response to oncogenic MYC expression creates dependency on MYC-driven metabolic pathways, which in principle provides novel targets for development of effective cancer therapeutics. In the current review, we summarize the significant progress made toward understanding how MYC deregulation fuels metabolic rewiring in malignant transformation.

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Section: Myc Regulation Of Lipid Metabolismmentioning

confidence: 99%

Section: Myc Regulation Of Lipid Metabolismmentioning

confidence: 99%

Section: Myc Regulation Of Lipid Metabolismmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat

Dong

Liu

et al. 2020

Sig Transduct Target Ther

193

169

View full text Add to dashboard Cite

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“…Both MYC (Yue et al, 2017) and HIF-2α (Elorza et al, 2012) activate the expression of the amino acid transporter SLC7A5 to promote essential amino acid (EAA) uptake. Both MYC (Gouw et al, 2019;Casciano et al, 2020) and HIF-2α (Rankin et al, 2009;Qiu et al, 2015) regulate lipid metabolism.…”

Section: Myc and Hif Cooperate To Reprogram Cancer Cell Metabolism Anmentioning

confidence: 99%

Molecular Crosstalk Between MYC and HIF in Cancer

Li¹,

Sun²,

Qian

et al. 2020

Front. Cell Dev. Biol.

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The transcription factor c-MYC (MYC thereafter) is a global regulator of gene expression. It is overexpressed or deregulated in human cancers of diverse origins and plays a key role in the development of cancers. Hypoxia-inducible factors (HIFs), a central regulator for cells to adapt to low cellular oxygen levels, is also often overexpressed and activated in many human cancers. HIF mediates the primary transcriptional response of a wide range of genes in response to hypoxia. Earlier studies focused on the inhibition of MYC by HIF during hypoxia, when MYC is expressed at physiological level, to help cells survive under low oxygen conditions. Emerging evidence suggests that MYC and HIF also cooperate to promote cancer cell growth and progression. This review will summarize the current understanding of the complex molecular interplay between MYC and HIF.

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“…Future studies can be carried out to test the role of FATP3 in breast cancer. Previous studies have implicated increased both fatty acid uptake and β Oxidation in overall tumor aggressiveness and metastatic potential beyond MYC-inducible models 15,[65][66][67][68][69] . The tumors of the 4T1 family of cell lines, which vary in metastatic potential (4T1 > 4T07 > 67NR), were selected to assess whether our technique could associate differences in fatty acid uptake across tumors of varying metastatic potential 38 .…”

Section: Discussionmentioning

confidence: 99%

In vivo optical metabolic imaging of long-chain fatty acid uptake in orthotopic models of triple negative breast cancer

Madonna¹,

Duer

Lee³

et al. 2020

Preprint

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Targeting a tumor's metabolic dependencies is a clinically actionable therapeutic approach, but identifying subtypes of tumors likely to respond remains difficult. The use of lipids as a nutrient source is of particular importance, especially in breast cancer. Imaging techniques offer the opportunity to quantify nutrient use in preclinical models to aid in the development of new drugs to restrict uptake or utilization of these nutrients. We describe a fast and dynamic approach to image fatty acid uptake in vivo, a tool relevant to study tumor metabolic reprogramming or for studying the effectiveness of drugs targeting lipid metabolism spanning beyond breast cancer and optical imaging alone. Specifically, we developed a quantitative optical approach to spatially and longitudinally map the kinetics of long-chain fatty acid uptake in in vivo murine models of breast cancer using a fluorescently labeled palmitate molecule, Bodipy FL c16. We chose intra-vital microscopy of mammary tumor windows to validate our approach in two orthotopic breast cancer models: a MYC-overexpressing transgenic triple-negative breast cancer (TNBC) model and a murine model of the 4T1 family. Following injection, Bodipy FL c16 fluorescence increased and reached its maximum after approximately 30 minutes, with the signal remaining stable during the 30-80-minute post-injection period. We used the fluorescence at 60 minutes (Bodipy60), the mid-point in the plateau region, as a summary parameter to quantify Bodipy FL c16 fluorescence in subsequent experiments. Using our imaging platform, we observed a two- to four-fold decrease in fatty acid uptake in response to the downregulation of the MYC oncogene consistent with findings from in vitro metabolic assays. In contrast, our imaging studies report an increase in fatty acid uptake with tumor aggressiveness (6NR, 4T07, and 4T1), and uptake was significantly decreased after treatment with a fatty acid transport inhibitor, perphenazine, in both normal mammary pads and in the most aggressive 4T1 tumor model. Our approach fills an important gap between in vitro assays, which provide rich metabolic information but at static time points, and imaging approaches that can visualize metabolism in whole organs, but which suffer from poor resolution.

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MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer

Cited by 59 publications

References 86 publications

Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat

Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat

Molecular Crosstalk Between MYC and HIF in Cancer

In vivo optical metabolic imaging of long-chain fatty acid uptake in orthotopic models of triple negative breast cancer

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