scholarly journals Breast Cancer Subtypes Underlying EMT-Mediated Catabolic Metabolism

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2064
Author(s):  
Eunae Cho ◽  
Nam Kim ◽  
Jun Yun ◽  
Sue Cho ◽  
Hyun Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metabolism ◽  
Metastatic Cancer ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Breast Cancer Subtypes ◽  
Clinical Samples ◽  
Acid Oxidation ◽  
Mesenchymal Transition ◽  
Cancer Subtypes ◽  
Mitochondrial Fatty Acid

Efficient catabolic metabolism of adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) is essentially required for cancer cell survival, especially in metastatic cancer progression. Epithelial–mesenchymal transition (EMT) plays an important role in metabolic rewiring of cancer cells as well as in phenotypic conversion and therapeutic resistance. Snail (SNAI1), a well-known inducer of cancer EMT, is critical in providing ATP and NADPH via suppression of several gatekeeper genes involving catabolic metabolism, such as phosphofructokinase 1 (PFK1), fructose-1,6-bisphosphatase 1 (FBP1), and acetyl-CoA carboxylase 2 (ACC2). Paradoxically, PFK1 and FBP1 are counter-opposing and rate-limiting reaction enzymes of glycolysis and gluconeogenesis, respectively. In this study, we report a distinct metabolic circuit of catabolic metabolism in breast cancer subtypes. Interestingly, PFKP and FBP1 are inversely correlated in clinical samples, indicating different metabolic subsets of breast cancer. The luminal types of breast cancer consist of the pentose phosphate pathway (PPP) subset by suppression of PFKP while the basal-like subtype (also known as triple negative breast cancer, TNBC) mainly utilizes glycolysis and mitochondrial fatty acid oxidation (FAO) by loss of FBP1 and ACC2. Notably, PPP remains active via upregulation of TIGAR in the FBP1-loss basal-like subset, indicating the importance of PPP in catabolic cancer metabolism. These results indicate different catabolic metabolic circuits and thus therapeutic strategies in breast cancer subsets.

scholarly journals Expanding Roles of De Novo Lipogenesis in Breast Cancer

2021 ◽  
Vol 18 (7) ◽  
pp. 3575
Author(s):  
Pasquale Simeone ◽  
Stefano Tacconi ◽  
Serena Longo ◽  
Paola Lanuti ◽  
Sara Bravaccini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
De Novo ◽  
Breast Cancer Subtypes ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Breast Cancer Patients ◽  
Membrane Composition ◽  
Lipogenic Enzymes ◽  
Cancer Subtypes

In recent years, lipid metabolism has gained greater attention in several diseases including cancer. Dysregulation of fatty acid metabolism is a key component in breast cancer malignant transformation. In particular, de novo lipogenesis provides the substrate required by the proliferating tumor cells to maintain their membrane composition and energetic functions during enhanced growth. However, it appears that not all breast cancer subtypes depend on de novo lipogenesis for fatty acid replenishment. Indeed, while breast cancer luminal subtypes rely on de novo lipogenesis, the basal-like receptor-negative subtype overexpresses genes involved in the utilization of exogenous-derived fatty acids, in the synthesis of triacylglycerols and lipid droplets, and fatty acid oxidation. These metabolic differences are specifically associated with genomic and proteomic changes that can perturb lipogenic enzymes and related pathways. This behavior is further supported by the observation that breast cancer patients can be stratified according to their molecular profiles. Moreover, the discovery that extracellular vesicles act as a vehicle of metabolic enzymes and oncometabolites may provide the opportunity to noninvasively define tumor metabolic signature. Here, we focus on de novo lipogenesis and the specific differences exhibited by breast cancer subtypes and examine the functional contribution of lipogenic enzymes and associated transcription factors in the regulation of tumorigenic processes.

scholarly journals Mammary epithelial cells have lineage-restricted metabolic identities

2019 ◽  
Author(s):  
Mathepan Mahendralingam ◽  
Kazeera Aliar ◽  
Alison Elisabeth Casey ◽  
Davide Pellacani ◽  
Hyeyeon Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial Cells ◽  
Oxidative Phosphorylation ◽  
Metabolic Network ◽  
Cancer Metabolism ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Breast Cancer Subtypes ◽  
Cell Of Origin ◽  
Cancer Subtypes

ABSTRACTCancer metabolism adapts the metabolic network of its tissue-of-origin. However, breast cancer is not a disease of a singular origin. Multiple epithelial populations serve as the culprit cell-of-origin for specific breast cancer subtypes, yet knowledge surrounding the metabolic network of normal mammary epithelial cells is limited. Here, we show that mammary populations have cell type-specific metabolic programs. Primary human breast cell proteomes of basal, luminal progenitor, and mature luminal populations revealed their unique enrichment of metabolic proteins. Luminal progenitors had higher abundance of electron transport chain subunits and capacity for oxidative phosphorylation, whereas basal cells were more glycolytic. Targeting oxidative phosphorylation and glycolysis with inhibitors exposed distinct metabolic vulnerabilities of the mammary lineages. Computational analysis indicated that breast cancer subtypes retain metabolic features of their putative cell-of-origin. Lineage-restricted metabolic identities of normal mammary cells partly explain breast cancer metabolic heterogeneity and rationalize targeting subtype-specific metabolic vulnerabilities to advance breast cancer therapy.

scholarly journals CRISPR/Cas9-mediated Bag-1 knockout increased mesenchymal characteristics of MCF-7 cells via Akt hyperactivation-mediated actin cytoskeleton remodeling

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0261062
Author(s):  
Pelin Ozfiliz Kilbas ◽  
Nisan Denizce Can ◽  
Tugba Kizilboga ◽  
Fikret Ezberci ◽  
Hamdi Levent Doganay ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Cancer ◽  
Normal Breast ◽  
Akt Inhibitor ◽  
Mesenchymal Transition ◽  
Cancer Subtypes ◽  
Akt Activation ◽  
Cytoskeleton Organization ◽  
Cytoskeleton Remodeling ◽  
Mcf 7

Bag-1 protein is a crucial target in cancer to increase the survival and proliferation of cells. The Bag-1 expression is significantly upregulated in primary and metastatic cancer patients compared to normal breast tissue. Overexpression of Bag-1 decreases the efficiency of conventional chemotherapeutic drugs, whereas Bag-1 silencing enhances the apoptotic efficiency of therapeutics, mostly in hormone-positive breast cancer subtypes. In this study, we generated stable Bag-1 knockout (KO) MCF-7 breast cancer cells to monitor stress-mediated cellular alterations in comparison to wild type (wt) and Bag-1 overexpressing (Bag-1 OE) MCF-7 cells. Validation and characterization studies of Bag-1 KO cells showed different cellular morphology with hyperactive Akt signaling, which caused stress-mediated actin reorganization, focal adhesion decrease and led to mesenchymal characteristics in MCF-7 cells. A potent Akt inhibitor, MK-2206, suppressed mesenchymal transition in Bag-1 KO cells. Similar results were obtained following the recovery of Bag-1 isoforms (Bag-1S, M, or L) in Bag-1 KO cells. The findings of this study emphasized that Bag-1 is a mediator of actin-mediated cytoskeleton organization through regulating Akt activation.

scholarly journals Differential expression of the BCAT isoforms between breast cancer subtypes

Breast Cancer ◽  
2020 ◽  
Author(s):  
Mai Ahmed Shafei ◽  
Arwa Flemban ◽  
Carl Daly ◽  
Paul Kendrick ◽  
Paul White ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metabolism ◽  
Breast Cancer Subtypes ◽  
Metabolic Phenotype ◽  
Luminal A ◽  
Cancer Subtypes ◽  
Luminal B ◽  
Treatment Regimens ◽  
Enhanced Expression ◽  
Branched Chain

Abstract Background Biological characterisation of breast cancer subtypes is essential as it informs treatment regimens especially as different subtypes have distinct locoregional patterns. This is related to metabolic phenotype, where altered cellular metabolism is a fundamental adaptation of cancer cells during rapid proliferation. In this context, the metabolism of the essential branched-chain amino acids (BCAAs), catalysed by the human branched-chain aminotransferase proteins (hBCAT), offers multiple benefits for tumour growth. Upregulation of the cytosolic isoform of hBCAT (hBCATc), regulated by c-Myc, has been demonstrated to increase cell migration, tumour aggressiveness and proliferation in gliomas, ovarian and colorectal cancer but the importance of the mitochondrial isoform, hBCATm has not been fully investigated. Methods Using immunohistochemistry, the expression profile of metabolic proteins (hBCAT, IDH) was assessed between breast cancer subtypes, HER2 + , luminal A, luminal B and TNBC. Correlations between the percentage and the intensity of protein expression/co-expression with clinical parameters, such as hormone receptor status, tumour stage, lymph-node metastasis and survival, were determined. Results We show that hBCATc expression was found to be significantly associated with the more aggressive HER2 + and luminal B subtypes, whilst hBCATm and IDH1 associated with luminal A subtype. This was concomitant with better prognosis indicating a differential metabolic reliance between these two subtypes, in which enhanced expression of IDH1 may replenish the α-ketoglutarate pool in cells with increased hBCATm expression. Conclusion The cytosolic isoform of BCAT is associated with tumours that express HER2 receptors, whereas the mitochondrial isoform is highly expressed in tumours that are ER + , indicating that the BCAT proteins are regulated through different signalling pathways, which may lead to the identification of novel targets for therapeutic applications targeting dysregulated cancer metabolism.

Identification of new therapeutic leads for triple negative breast cancer subtypes

Planta Medica ◽  
2015 ◽  
Vol 81 (11) ◽  
Author(s):  
AJ Robles ◽  
L Du ◽  
S Cai ◽  
RH Cichewicz ◽  
SL Mooberry
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Subtypes ◽  
Cancer Subtypes ◽  
Therapeutic Leads
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