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Understanding and Modelling Metabolic Reprogramming in Breast Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 24927

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Special Issue Editors

Dr. Gorrini Chiara

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Guest Editor

Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
Interests: breast cancer; tumour microenvironment; cancer metabolism; oxidative stress; immune system; cancer models; bioengineering

Prof. Dr. Jason Matthews

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Guest Editor

Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
Interests: breast cancer; tumour microenvironment; oxidative stress; immune system; ADP-ribosylation; inflammation; cancer models

Special Issue Information

Dear Colleagues,

Deregulated cellular metabolism is a hallmark of breast cancer and a critical feature of breast neoplastic progression. Similar to other cancer types, breast cancer, compared with healthy tissues, is characterized by elevated levels of aerobic glycolysis, glutaminolysis and heightened flux through the pentose phosphate pathway. These features are both temporally and spatially tunable, allowing tumour cells to react to cues and stresses originating in their internal and local environments. This metabolic flexibility inevitably causes a high degree of heterogeneity that poses a great challenge for therapies against metabolic vulnerabilities.

Understanding and dissecting breast cancer metabolic networks is a complex problem that calls for multidisciplinary approaches. This Special Issue will bring together scientists from diverse disciplines such as cell biology, computer science, immunology, physics and bioengineering worlds. The goal is to harness breast cancer metabolism through the acquisition of a highly comprehensive knowledge and the generation of cellular models that closely mimic the metabolic aspects of this disease.

Dr. Gorrini Chiara
Prof. Dr. Jason Matthews
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cancer metabolism
oxidative stress
3D models
tumour microenvironment
heterogeneity
imaging
modelling

Published Papers (7 papers)

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Research

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16 pages, 2897 KiB

Open AccessArticle

The Antiviral Drug Efavirenz in Breast Cancer Stem Cell Therapy

by Pey-Tsyr Chiou, Stephen Ohms, Philip G. Board, Jane E. Dahlstrom, Danny Rangasamy and Marco G. Casarotto

Cancers 2021, 13(24), 6232; https://doi.org/10.3390/cancers13246232 - 11 Dec 2021

Cited by 1 | Viewed by 2544

Abstract

Although many breast cancer therapies show initial success in the treatment of the primary tumour, they often fail to eliminate a sub-population of cells known as cancer stem cells (CSCs). These cells are recognised for their self-renewal properties and for their capacity for differentiation often leading to chemo/radio-resistance. The antiviral drug Efavirenz has been shown to be effective in eliminating triple-negative breast cancer cells, and here we examine its effect on breast CSCs. The effects of Efavirenz on CSCs for several breast cancer cell lines were investigated by examining cellular changes upon drug treatment, including CSC numbers, morphology, RNA/microRNA expression and levels of epithelial/mesenchymal CSC subtypes. Efavirenz treatment resulted in a decrease in the size and number of tumorspheres and a reduction in epithelial-type CSC levels, but an increase in mesenchymal-type CSCs. Efavirenz caused upregulation of several CSC-related genes as well as miR-21, a CSC marker and miR-182, a CSC suppressor gene. We conclude that Efavirenz alters the phenotype and expression of key genes in breast CSCs, which has important potential therapeutic implications. Full article

(This article belongs to the Special Issue Understanding and Modelling Metabolic Reprogramming in Breast Cancer)

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14 pages, 4579 KiB

Open AccessArticle

Targeting Amino Acid Metabolic Reprogramming via L-Type Amino Acid Transporter 1 (LAT1) for Endocrine-Resistant Breast Cancer

by Haruhiko Shindo, Narumi Harada-Shoji, Akiko Ebata, Miku Sato, Tomoyoshi Soga, Minoru Miyashita, Hiroshi Tada, Masaaki Kawai, Shinkichi Kosaka, Koji Onuki, Shin Usami, Shozo Furumoto, Shinichi Hayashi, Takaaki Abe, Takashi Suzuki, Takanori Ishida and Hironobu Sasano

Cancers 2021, 13(17), 4375; https://doi.org/10.3390/cancers13174375 - 30 Aug 2021

Cited by 13 | Viewed by 2917

Abstract

The PI3K/Akt/mTOR pathway has been well known to interact with the estrogen receptor (ER)-pathway and to be also frequently upregulated in aromatase inhibitor (AI)-resistant breast cancer patients. Intracellular levels of free amino acids, especially leucine, regulate the mammalian target of rapamycin complex 1 (mTORC1) activation. L-type amino acid transporters such as LAT1 and LAT3 are associated with the uptake of essential amino acids. LAT1 expression could mediate leucine uptake, mTORC1 signaling, and cell proliferation. Therefore, in this study, we explored amino acid metabolism, including LAT1, in breast cancer and clarified the potential roles of LAT1 in the development of therapeutic resistance and the eventual clinical outcome of the patients. We evaluated LAT1 and LAT3 expression before and after neoadjuvant hormone therapy (NAH) and examined LAT1 function and expression in estrogen deprivation-resistant (EDR) breast carcinoma cell lines. Tumors tended to be in advanced stages in the cases whose LAT1 expression was high. LAT1 expression in the EDR cell lines was upregulated. JPH203, a selective LAT1 inhibitor, demonstrated inhibitory effects on cell proliferation in EDR cells. Hormone therapy changed the tumor microenvironment and resulted in metabolic reprogramming through inducing LAT1 expression. LAT1 expression then mediated leucine uptake, enhanced mTORC1 signaling, and eventually resulted in AI resistance. Therefore, LAT1 could be the potential therapeutic target in AI-resistant breast cancer patients. Full article

(This article belongs to the Special Issue Understanding and Modelling Metabolic Reprogramming in Breast Cancer)

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19 pages, 3814 KiB

Open AccessArticle

The Biological and Clinical Significance of Glutaminase in Luminal Breast Cancer

by Brendah K. Masisi, Rokaya El Ansari, Lutfi Alfarsi, Madeleine L. Craze, Natasha Jewa, Andrew Oldfield, Hayley Cheung, Michael Toss, Emad A. Rakha and Andrew R. Green

Cancers 2021, 13(16), 3963; https://doi.org/10.3390/cancers13163963 - 6 Aug 2021

Cited by 10 | Viewed by 2518

Abstract

The glutamine metabolism has a key role in the regulation of uncontrolled tumour growth. This study aimed to evaluate the expression and prognostic significance of glutaminase in luminal breast cancer (BC). The glutaminase isoforms (GLS/GLS2) were assessed at genomic/transcriptomic levels, using METABRIC (n = 1398) and GeneMiner datasets (n = 4712), and protein using immunohistochemistry in well-characterised cohorts of Oestrogen receptor-positive/HER2-negative BC patients: ductal carcinoma in situ (DCIS; n = 206) and invasive breast cancer (IBC; n = 717). Glutaminase expression was associated with clinicopathological features, patient outcome and glutamine-metabolism-related genes. In DCIS, GLS alone and GLS+/GLS2- expression were risk factors for shorter local recurrence-free interval (p < 0.0001 and p = 0.001, respectively) and remained prognostic factors independent of tumour size, grade and comedo necrosis (p = 0.0008 and p = 0.003, respectively). In IBC, GLS gene copy number gain with high mRNA expression was associated with poor patient outcome (p = 0.011), whereas high GLS2 protein was predictive of a longer disease-free survival (p = 0.006). Glutaminase plays a role in the biological function of luminal BC, particularly GLS in the early non-invasive stage, which could be used as a potential biomarker to predict disease progression and a target for inhibition. Further validation is required to confirm these observations, and functional assessments are needed to explore their specific roles. Full article

(This article belongs to the Special Issue Understanding and Modelling Metabolic Reprogramming in Breast Cancer)

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25 pages, 3268 KiB

Open AccessArticle

Cholesterol-Induced Metabolic Reprogramming in Breast Cancer Cells Is Mediated via the ERRα Pathway

by Faegheh Ghanbari, Anne-Marie Fortier, Morag Park and Anie Philip

Cancers 2021, 13(11), 2605; https://doi.org/10.3390/cancers13112605 - 26 May 2021

Cited by 11 | Viewed by 3282

Abstract

The molecular mechanism underlying the metabolic reprogramming associated with obesity and high blood cholesterol levels is poorly understood. We previously reported that cholesterol is an endogenous ligand of the estrogen-related receptor alpha (ERRα). Using functional assays, metabolomics, and genomics, here we show that exogenous cholesterol alters the metabolic pathways in estrogen receptor-positive (ER+) and triple-negative breast cancer (TNBC) cells, and that this involves increased oxidative phosphorylation (OXPHOS) and TCA cycle intermediate levels. In addition, cholesterol augments aerobic glycolysis in TNBC cells although it remains unaltered in ER+ cells. Interestingly, cholesterol does not alter the metabolite levels of glutaminolysis, one-carbon metabolism, or the pentose phosphate pathway, but increases the NADPH levels and cellular proliferation, in both cell types. Importantly, we show that the above cholesterol-induced modulations of the metabolic pathways in breast cancer cells are mediated via ERRα. Furthermore, analysis of the ERRα metabolic gene signature of basal-like breast tumours of overweight/obese versus lean patients, using the GEO database, shows that obesity may modulate ERRα gene signature in a manner consistent with our in vitro findings with exogenous cholesterol. Given the close link between high cholesterol levels and obesity, our findings provide a mechanistic explanation for the association between cholesterol/obesity and metabolic reprogramming in breast cancer patients. Full article

(This article belongs to the Special Issue Understanding and Modelling Metabolic Reprogramming in Breast Cancer)

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Review

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34 pages, 1631 KiB

Open AccessEditor’s ChoiceReview

Pathophysiological Integration of Metabolic Reprogramming in Breast Cancer

by Roberto Corchado-Cobos, Natalia García-Sancha, Marina Mendiburu-Eliçabe, Aurora Gómez-Vecino, Alejandro Jiménez-Navas, Manuel Jesús Pérez-Baena, Marina Holgado-Madruga, Jian-Hua Mao, Javier Cañueto, Sonia Castillo-Lluva and Jesús Pérez-Losada

Cancers 2022, 14(2), 322; https://doi.org/10.3390/cancers14020322 - 10 Jan 2022

Cited by 9 | Viewed by 4084

Abstract

Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. The triggers of these metabolic changes are located in the tumor parenchymal cells, where oncogenic mutations induce an imperative need to proliferate and cause tumor initiation and progression. Cancer cells undergo significant metabolic reorganization during disease progression that is tailored to their energy demands and fluctuating environmental conditions. Oxidative stress plays an essential role as a trigger under such conditions. These metabolic changes are the consequence of the interaction between tumor cells and stromal myofibroblasts. The metabolic changes in tumor cells include protein anabolism and the synthesis of cell membranes and nucleic acids, which all facilitate cell proliferation. They are linked to catabolism and autophagy in stromal myofibroblasts, causing the release of nutrients for the cells of the tumor parenchyma. Metabolic changes lead to an interstitium deficient in nutrients, such as glucose and amino acids, and acidification by lactic acid. Together with hypoxia, they produce functional changes in other cells of the tumor stroma, such as many immune subpopulations and endothelial cells, which lead to tumor growth. Thus, immune cells favor tissue growth through changes in immunosuppression. This review considers some of the metabolic changes described in breast cancer. Full article

(This article belongs to the Special Issue Understanding and Modelling Metabolic Reprogramming in Breast Cancer)

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19 pages, 1840 KiB

Open AccessReview

Metabolic Flexibility Is a Determinant of Breast Cancer Heterogeneity and Progression

by Marina Fukano, Morag Park and Geneviève Deblois

Cancers 2021, 13(18), 4699; https://doi.org/10.3390/cancers13184699 - 19 Sep 2021

Cited by 8 | Viewed by 3908

Abstract

Breast cancer progression is characterized by changes in cellular metabolism that contribute to enhanced tumour growth and adaptation to microenvironmental stresses. Metabolic changes within breast tumours are still poorly understood and are not as yet exploited for therapeutic intervention, in part due to a high level of metabolic heterogeneity within tumours. The metabolic profiles of breast cancer cells are flexible, providing dynamic switches in metabolic states to accommodate nutrient and energy demands and further aggravating the challenges of targeting metabolic dependencies in cancer. In this review, we discuss the intrinsic and extrinsic factors that contribute to metabolic heterogeneity of breast tumours. Next, we examine how metabolic flexibility, which contributes to the metabolic heterogeneity of breast tumours, can alter epigenetic landscapes and increase a variety of pro-tumorigenic functions. Finally, we highlight the difficulties in pharmacologically targeting the metabolic adaptations of breast tumours and provide an overview of possible strategies to sensitize heterogeneous breast tumours to the targeting of metabolic vulnerabilities. Full article

(This article belongs to the Special Issue Understanding and Modelling Metabolic Reprogramming in Breast Cancer)

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23 pages, 1145 KiB

Open AccessReview

Multi-Omic Approaches to Breast Cancer Metabolic Phenotyping: Applications in Diagnosis, Prognosis, and the Development of Novel Treatments

by Nuria Gómez-Cebrián, Inés Domingo-Ortí, José Luis Poveda, María J. Vicent, Leonor Puchades-Carrasco and Antonio Pineda-Lucena

Cancers 2021, 13(18), 4544; https://doi.org/10.3390/cancers13184544 - 10 Sep 2021

Cited by 9 | Viewed by 4207

Abstract

Breast cancer (BC) is characterized by high disease heterogeneity and represents the most frequently diagnosed cancer among women worldwide. Complex and subtype-specific gene expression alterations participate in disease development and progression, with BC cells known to rewire their cellular metabolism to survive, proliferate, and invade. Hence, as an emerging cancer hallmark, metabolic reprogramming holds great promise for cancer diagnosis, prognosis, and treatment. Multi-omics approaches (the combined analysis of various types of omics data) offer opportunities to advance our understanding of the molecular changes underlying metabolic rewiring in complex diseases such as BC. Recent studies focusing on the combined analysis of genomics, epigenomics, transcriptomics, proteomics, and/or metabolomics in different BC subtypes have provided novel insights into the specificities of metabolic rewiring and the vulnerabilities that may guide therapeutic development and improve patient outcomes. This review summarizes the findings of multi-omics studies focused on the characterization of the specific metabolic phenotypes of BC and discusses how they may improve clinical BC diagnosis, subtyping, and treatment. Full article

(This article belongs to the Special Issue Understanding and Modelling Metabolic Reprogramming in Breast Cancer)

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