Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation

Weverwijk, Antoinette van; Koundouros, Nikos; Iravani, Marjan; Ashenden, Matthew; Gao, Qiong; Poulogiannis, George; Jungwirth, Ute; Isacke, Clare M.

doi:10.1038/s41467-019-10592-4

Cited by 89 publications

(63 citation statements)

References 55 publications

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“…Cytotoxic therapy increased oxidative damage, which may kill tumor cells [ 30 ]. High oxidative stress created a challenging microenvironment for breast cancer metastasis [ 31 ]. However, the genes of module 5, which was negatively correlated with high immune infiltration, were mainly involved in Wnt signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Recognition of Immune Microenvironment Landscape and Immune-Related Prognostic Genes in Breast Cancer

Wang

You

Fang

et al. 2020

BioMed Research International

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Background. Breast cancer (BC) is the most common malignant tumor in women. The immunophenotype of tumor microenvironment (TME) has shown great therapeutic potential in tumor. Method. The transcriptome was obtained from TCGA and GEO data. Immune infiltration was analyzed by single-sample gene set enrichment (ssGSEA). The immune feature was constructed by Cox regression analysis. In addition, the coexpression of differential expression genes (DEGs) was identified. Through enrichment analysis, the function and pathway of module genes were identified. The somatic mutations related to immune characteristics were analyzed by Maftools. By using the consistency clustering algorithm, the molecular subtypes were constructed, and the overall survival time (OS) was predicted. Results. Immune landscape can be divided into low immune infiltration and high immune infiltration. Cox regression analysis identified seven immune cells as protective factors of BC. In the coexpression modules for DEGs of high and low immune infiltration, module 1 was related to T cells and high immune infiltration. In particular, the area under the curve (AUC) value of hub gene SASH3 was the highest, and the correlation with T cells was stronger in the high immune infiltration. Enrichment analysis found that oxidative stress, T cell aggregation, and apoptosis were observed in high immune infiltration. In addition, TP53 was identified as the most important somatic gene mutation related to immune characteristics. Importantly, we also constructed seven immune cell-based breast cancer subtypes to predict OS. Conclusion. We evaluated the immune landscape of BC and constructed the gene characteristics related to the immune landscape. The potential of T cells and SASH3 in immunotherapy of BC was revealed, which may guide the development of new clinical treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Recognition of Immune Microenvironment Landscape and Immune-Related Prognostic Genes in Breast Cancer

Wang

You

Fang

et al. 2020

BioMed Research International

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“…The fact that in vitro cancer cells behave remarkably different as compared with tumor microenvironments necessitates extensive studies to understand tumor heterogeneities, and to identify suitable molecular markers for types of stroma in order to predict treatment response in vivo . For example, an interesting recent report linked elevated aldo-keto reductase AKR1B10 expression in ER − and HER2 + breast cancers with an increased incidence of metastatic relapse at secondary sites that was associated with increased fatty acid utilization 61 . These authors determined that breast cancer cells with high AKR1B10 expression do not display altered survival or proliferation properties when cultured in vitro or when grown as primary tumors in the fat pads of recipient mice but are more robust when cultured in nutrient poor conditions or when colonizing the lungs.…”

Section: Discussionmentioning

confidence: 99%

Role of mitochondria in rescuing glycolytically inhibited subpopulation of triple negative but not hormone-responsive breast cancer cells

Reda

Refaat

Abdrabou

et al. 2019

Sci Rep

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Triple-negative breast cancer (TNBC) subtype is among the most aggressive cancers with the worst prognosis and least therapeutic targetability while being more likely to spread and recur. Cancer transformations profoundly alter cellular metabolism by increasing glucose consumption via glycolysis to support tumorigenesis. Here we confirm that relative to ER-positive cells (MCF7), TNBC cells (MBA-MD-231) rely more on glycolysis thus providing a rationale to target these cells with glycolytic inhibitors. Indeed, iodoacetate (IA), an effective GAPDH inhibitor, caused about 70% drop in MDA-MB-231 cell viability at 20 μM while 40 μM IA was needed to decrease MCF7 cell viability only by 30% within 4 hours of treatment. However, the triple negative cells showed strong ability to recover after 24 h whereas MCF7 cells were completely eliminated at concentrations <10 μM. To understand the mechanism of MDA-MB-231 cell survival, we studied metabolic modulations associated with acute and extended treatment with IA. The resilient TNBC cell population showed a significantly greater count of cells with active mitochondria, lower apoptotic markers, normal cell cycle regulations, moderately lowered ROS, but increased mRNA levels of p27 and PARP1; all compatible with enhanced cell survival. Our results highlight an interplay between PARP and mitochondrial oxidative phosphorylation in TNBC that comes into play in response to glycolytic disruption. In the light of these findings, we suggest that combined treatment with PARP and mitochondrial inhibitors may provide novel therapeutic strategy against TNBC.

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“…Etomoxir attenuates growth in AKR1B10-high tumor spheroids but not in the AKR1B10-high tumor spheroids. Thus, AKR1B10 may serve as a predictor of metastatic potential in TNBC and also as a target for future inhibitors in TNBC tumors (114). Another in vivo study reported impaired lung metastasis in myoferlin-deficient TNBC cells.…”

Section: Impact Of Metabolic Reprogramming On Tnbc Metastasismentioning

confidence: 99%

Metabolic Reprogramming in Triple-Negative Breast Cancer

et al. 2020

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Metabolic reprogramming is an emerging hallmark of cancer cells, in which cancer cells exhibit distinct metabolic phenotypes to fuel their proliferation and progression. The significant advancements made in the area of metabolic reprogramming make possible new strategies for overcoming malignant cancer, including triple-negative breast cancer. Triple-negative breast cancer (TNBC) is associated with high histologic grade, aggressive phenotype, and poor prognosis. Even though triple-negative breast cancer patients benefit from standard chemotherapy, they still face high recurrence rates and are more likely to develop resistance to chemotherapeutic drugs. Therefore, there is an urgent need to explore vulnerabilities of triple-negative breast cancer and develop novel therapeutic drugs to improve clinical outcomes for triple-negative breast cancer patients. Metabolic reprogramming may provide promising therapeutic targets for the treatment of triple-negative breast cancer. In this paper, we primarily discuss how triple-negative breast cancer cells reprogram their metabolic phenotype and that of stromal cells in the microenvironment to survive under nutrient-poor conditions. Considering that metastasis and chemoresistance are the main contributors to mortality in triple-negative breast cancer patients, we also focus on the role of metabolic adaption in mediating metastasis and chemoresistance of triple-negative breast cancer tumors.

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Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation

Cited by 89 publications

References 55 publications

Recognition of Immune Microenvironment Landscape and Immune-Related Prognostic Genes in Breast Cancer

Recognition of Immune Microenvironment Landscape and Immune-Related Prognostic Genes in Breast Cancer

Role of mitochondria in rescuing glycolytically inhibited subpopulation of triple negative but not hormone-responsive breast cancer cells

Metabolic Reprogramming in Triple-Negative Breast Cancer

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