Deciphering metabolic rewiring in breast cancer subtypes

Ogrodzinski, Martin P.; Bernard, Jamie J.; Lunt, Sophia Y.

doi:10.1016/j.trsl.2017.07.004

Cited by 49 publications

(43 citation statements)

References 215 publications

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“…However, the possibility of inadvertently stimulating tumor growth by improperly targeting metabolism should also be considered further, especially in recognition of the significant heterogeneity of breast cancer. Further work should be directed at determining whether subtypes of human breast cancer, which are known to exhibit different metabolic features (Ogrodzinski et al, 2017), have differences in metabolic vulnerabilities, and whether targeting non-preferred pathways is detrimental.…”

Section: Discussionmentioning

confidence: 99%

“…However, targeted therapies are not available for all subtypes of breast cancer, and current rates of recurrence and development of resistance remain problematic (Early Breast Cancer Trialists' Collaborative, 2005, Gonzalez-Angulo et al, 2007. It is becoming increasingly clear that breast cancer subtypes have differences in metabolism, and targeting these metabolic pathways could provide new targeted therapy options (Ogrodzinski et al, 2017, Luengo et al, 2017.…”

Section: Introductionmentioning

confidence: 99%

“…However, one of the challenges in using metabolic rewiring to treat cancer arises from the fact that cancer is a remarkably heterogenous disease, and few metabolic vulnerabilities are common to all cancers. This variability is clearly illustrated by breast cancer, which demonstrates heterogeneity on histologic, genetic, and metabolic levels (Perou et al, 2000, Sørlie et al, 2001, Ellis et al, 1992, Ogrodzinski et al, 2017.…”

Section: Introductionmentioning

confidence: 99%

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Targeting subtype-specific metabolic preferences in nucleotide biosynthesis inhibits tumor growth in a breast cancer model

Ogrodzinski¹,

Teoh²,

Lunt³

2020

Preprint

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Investigating metabolic rewiring in cancer can lead to the discovery of new treatment strategies for breast cancer subtypes that currently lack targeted therapies. Using MMTV-Myc driven tumors to model breast cancer heterogeneity, we investigated metabolic differences between two histological subtypes, the epithelial-mesenchymal transition (EMT) and the papillary subtypes, using a combination of genomic and metabolomic techniques. We identified differences in nucleotide metabolism between EMT and papillary subtypes: EMT tumors preferentially use the nucleotide salvage pathway, while papillary tumors prefer de novo nucleotide biosynthesis. Using CRISPR/Cas9 gene editing and mass spectrometry-based methods, we determined that targeting the preferred pathway in each subtype resulted in greater metabolic impact than targeting the non-preferred pathway. We further show that knocking out the preferred nucleotide pathway in each subtype has a deleterious effect on in vivo tumor growth. In contrast, knocking out the non-preferred pathway has a lesser effect or results in increased tumor growth.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting subtype-specific metabolic preferences in nucleotide biosynthesis inhibits tumor growth in a breast cancer model

Ogrodzinski¹,

Teoh²,

Lunt³

2020

Preprint

Self Cite

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“…For exploring the therapeutic potential of metabolic targeting, numerous studies were conducted to examine how cellular metabolisms are rewired in different molecular subtypes of breast cancer. Their findings have shown that each subtype of breast cancer displays distinct metabolic alterations [4]. For example, TNBCs and HER2-positive breast cancers manifest higher glycolytic activity (Warburg effect) and glutamine metabolism compared to luminal breast cancers.…”

Section: Introductionmentioning

confidence: 99%

FOXF2 differentially regulates expression of metabolic genes in non-cancerous and cancerous breast epithelial cells

2018

Trends Diabetes Metab

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Forkhead box F2 (FOXF2) functions as a transcription factor and is critically involved in programming organogenesis and regulating epithelial-to-mesenchymal transition (EMT) and cell proliferation. We recently have revealed that FOXF2 can exert distinct functional effects on different molecular subtypes of breast cancer. We found that FOXF2 expression is epigenetically silenced in luminal breast cancers due to its tumor-suppressive role in DNA replication regulation. In contrast, FOXF2 is overexpressed in basal-like triple-negative breast cancers (TNBCs) due to its oncogenic role in promoting EMT. Although our and other studies have shown that FOXF2 dysregulation is critical for tumorigenesis of various tissue types, the role of FOXF2 in metabolic rewiring of cancer remains unknown. In this study, we analyzed our previous microarray data to understand the metabolic role of FOXF2 in non-cancerous and cancerous breast epithelial cells. Our studies showed that in non-cancerous breast epithelial cells FOXF2 can also play a dual role either in tumor suppression or in tumor promotion through regulating expression of tumor-suppressive and oncogenic metabolic genes. Furthermore, we found that FOXF2-regulated metabolic genes are not conserved between non-cancerous and cancerous breast epithelial cells and FOXF2 is involved in metabolic rewiring in breast cancer cells. This is the first report to explore the metabolic function of FOXF2 in breast cancer.

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“…The non-oxidative arm of the pentose phosphate pathway generates ribose-5-185 phosphate, which is used to produce new nucleotides for DNA and RNA synthesis ( adaptive responses can be linked to the ability of cancer cells to gain resistance to certain 226 therapies, identification of specific metabolic vulnerabilities is also viewed as a potential 227 way of identifying new opportunities for cancer treatments (Luengo, et al 2017 and breast cancer and are summarized in Figure 1. The prevailing consensus within the field 239 is that while these metabolic reprogramming events might not be the initiating stimulus for 240 breast cancer cell transformation in isolation, they create the metabolic phenotype that is 241 required for high proliferative rates and resistance to cell death and are therefore essential 242 topic), however it should be noted that distinct metabolic phenotypes have been observed 253 in different breast cancer sub-types (Ogrodzinski, et al 2017). Therefore, it is intuitive that 254 the mechanism(s) by which type 2 diabetes might impact on the development of breastcancer will differ markedly for different breast cancers.…”

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confidence: 99%

Metabolic reprogramming in type 2 diabetes and the development of breast cancer

Martin

McGee

2018

Journal of Endocrinology

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A wealth of epidemiological data has found that patients with type 2 diabetes have a greater risk of developing breast cancer. The molecular mechanisms underpinning this relationship are yet to be elucidated; however, this review examines the available evidence suggesting that the metabolic abnormalities observed in type 2 diabetes can predispose to the development of breast cancer. Alterations in substrate availability and the hormonal milieu, particularly hyperinsulinemia, not only create a favorable metabolic environment for tumorigenesis, but also induce metabolic reprogramming events that are required for the transformation of breast cancer cells. In addition, the dysfunction and hypoxia of adipose tissue surrounding the breast cancer niche is another putative link that will be discussed. Finally, the mechanisms by which breast cancer cells evade checkpoints associated with nutrient overload will be examined. Experimentally validating these potential links will be important for prediction and treatment of breast cancer in patients with type 2 diabetes.

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Deciphering metabolic rewiring in breast cancer subtypes

Cited by 49 publications

References 215 publications

Targeting subtype-specific metabolic preferences in nucleotide biosynthesis inhibits tumor growth in a breast cancer model

Targeting subtype-specific metabolic preferences in nucleotide biosynthesis inhibits tumor growth in a breast cancer model

FOXF2 differentially regulates expression of metabolic genes in non-cancerous and cancerous breast epithelial cells

Metabolic reprogramming in type 2 diabetes and the development of breast cancer

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