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A tumour suppressive relationship between mineralocorticoid and retinoic acid receptors activates a transcriptional program consistent with a reverse Warburg effect in breast cancer.

ABSTRACT: BACKGROUND:The role of nuclear receptors in both the aetiology and treatment of breast cancer is exemplified by the use of the oestrogen receptor (ER) as a prognostic marker and treatment target. Treatments targeting the oestrogen signalling pathway are initially highly effective for most patients. However, for the breast cancers that fail to respond, or become resistant, to current endocrine treatments, the long-term outlook is poor. ER is a member of the nuclear receptor superfamily, comprising 48 members in the human, many of which are expressed in the breast and could be used as alternative targets in cases where current treatments are ineffective. METHODS:We used sparse canonical correlation analysis to interrogate potential novel nuclear receptor expression relationships in normal breast and breast cancer. These were further explored using whole transcriptome profiling in breast cancer cells after combinations of ligand treatments. RESULTS:Using this approach, we discovered a tumour suppressive relationship between the mineralocorticoid receptor (MR) and retinoic acid receptors (RAR), in particular RAR?. Expression profiling of MR expressing breast cancer cells revealed that mineralocorticoid and retinoid co-treatment activated an expression program consistent with a reverse Warburg effect and growth inhibition, which was not observed with either ligand alone. Moreover, high expression of both MR and RARB was associated with improved breast cancer-specific survival. CONCLUSION:Our study reveals a previously unknown relationship between MR and RAR in the breast, which is dependent on menopausal state and altered in malignancy. This finding identifies potential new targets for the treatment of breast cancers that are refractory to existing therapeutic options.

SUBMITTER: Doan TB

PROVIDER: S-EPMC7641839 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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A tumour suppressive relationship between mineralocorticoid and retinoic acid receptors activates a transcriptional program consistent with a reverse Warburg effect in breast cancer.

Doan Tram B TB Cheung Vanessa V Clyne Colin D CD Hilton Heidi N HN Eriksson Natalie N Young Morag J MJ Funder John W JW Muscat George E O GEO Fuller Peter J PJ Clarke Christine L CL Graham J Dinny JD

Breast cancer research : BCR 20201104 1

<h4>Background</h4>The role of nuclear receptors in both the aetiology and treatment of breast cancer is exemplified by the use of the oestrogen receptor (ER) as a prognostic marker and treatment target. Treatments targeting the oestrogen signalling pathway are initially highly effective for most patients. However, for the breast cancers that fail to respond, or become resistant, to current endocrine treatments, the long-term outlook is poor. ER is a member of the nuclear receptor superfamily, c ...[more]

PMID: 33148314

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Project description:BackgroundAcute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. It can be caused by mutations that turn on oncogenes or turn off tumour suppressor genes. For instance, changes in certain genes including Rb and p53 are common in ALL cells. Oncogenes and TSGs may serve as a modulator gene to regulate the gene expression level via their respective target genes. To investigate the regulatory relationship between oncogenes, tumour suppressor genes and transcription factors at the post translational level in childhood ALL, we performed an integrative network analysis on the gene regulation in the post-translational level for childhood ALL based on many publicly available cancer gene expression data including TARGET and GEO database.MethodsWe collected 259 childhood ALL-related genes from the latest online leukemia database, Leukemia Gene Literature Database. These 259 genes were selected from a comprehensive systematic literature with experimental evidences. The identified and curated genes were also associated with patient survival cases and we incorporated this pediatric ALL-related gene list into our analysis. We extracted the known human TFs from the TRRUST database. Among 259 childhood ALL-related genes, 101 unique regulators were mapped to the list of oncogene and tumour suppressor genes (TSGs) from the ONGene and the TSGene databases, and these included 74 TSGs, 62 oncogenes and 46 TF genes.ResultsThe resulted regulation was presented as a hierarchical regulatory network with transcription factors (TFs) as intermediate regulators connecting the top modulators (oncogene and TSGs) to the common target genes. Cross-validation was applied to the results from the TARGET dataset by identifying the consistent regulatory motifs based on three independent ALL expression datasets. A three-layer regulatory network of consistent positive modulators in childhood ALL was constructed in which 74 modulators (40 oncogenes, 34 TSGs) are considered as the most important regulators. The middle layer and the bottom layer contain 34 TFs and 176 target genes, respectively. Oncogenes mostly participated in positive regulation of gene expression and the transcription process of RNA II polymerase, while TSGs were mainly involved in the negative regulation of gene expression. In addition, the oncogene-specific targets were enriched with regulators of the MAPK cascade while tumour suppressor-specific targets were associated with cell death.ConclusionThe results revealed that oncogenes and TSGs possess a different functional regulatory pattern with regard to not only their biological functions but also their specific target genes in childhood ALL cancer progression. Taken together, our findings could contribute to a better understanding of the important regulatory mechanisms and this method could be used to analyse the targeted genes at the post-translational level in childhood ALL through integrative network analysis.

Project description:Cancer metabolism has received renewed interest as a potential target for cancer therapy. In this study, we use a multi-scale modeling approach to interrogate the implications of three metabolic scenarios of potential clinical relevance: the Warburg effect, the reverse Warburg effect and glutamine addiction. At the intracellular level, we construct a network of central metabolism and perform flux balance analysis (FBA) to estimate metabolic fluxes; at the cellular level, we exploit this metabolic network to calculate parameters for a coarse-grained description of cellular growth kinetics; and at the multicellular level, we incorporate these kinetic schemes into the cellular automata of an agent-based model (ABM), iDynoMiCS. This ABM evaluates the reaction-diffusion of the metabolites, cellular division and motion over a simulation domain. Our multi-scale simulations suggest that the Warburg effect provides a growth advantage to the tumor cells under resource limitation. However, we identify a non-monotonic dependence of growth rate on the strength of glycolytic pathway. On the other hand, the reverse Warburg scenario provides an initial growth advantage in tumors that originate deeper in the tissue. The metabolic profile of stromal cells considered in this scenario allows more oxygen to reach the tumor cells in the deeper tissue and thus promotes tumor growth at earlier stages. Lastly, we suggest that glutamine addiction does not confer a selective advantage to tumor growth with glutamine acting as a carbon source in the tricarboxylic acid (TCA) cycle, any advantage of glutamine uptake must come through other pathways not included in our model (e.g., as a nitrogen donor). Our analysis illustrates the importance of accounting explicitly for spatial and temporal evolution of tumor microenvironment in the interpretation of metabolic scenarios and hence provides a basis for further studies, including evaluation of specific therapeutic strategies that target metabolism.

Dataset Information

A tumour suppressive relationship between mineralocorticoid and retinoic acid receptors activates a transcriptional program consistent with a reverse Warburg effect in breast cancer.

Publications

A tumour suppressive relationship between mineralocorticoid and retinoic acid receptors activates a transcriptional program consistent with a reverse Warburg effect in breast cancer.

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