The mevalonate precursor enzyme HMGCS1 is a novel marker and key mediator of cancer stem cell enrichment in luminal and basal models of breast cancer

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From: PLoS ONE(Vol. 15, Issue 7)
Publisher: Public Library of Science
Document Type: Report
Length: 7,560 words
Lexile Measure: 1540L

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Author(s): Claire A. Walsh 1, Nina Akrap 1, Elena Garre 1, Ylva Magnusson 1, Hannah Harrison 2, Daniel Andersson 1, Emma Jonasson 1, Svanheidur Rafnsdottir 3, Hani Choudhry 4, Francesca Buffa 5, Jiannis Ragoussis 6, Anders Ståhlberg 1,7,8, Adrian Harris 5, Göran Landberg 1,*

Introduction

Breast cancer is a distinctly heterogeneous disease, characterized by a complex and dynamic tumour cell population and a highly plastic tumour microenvironment [1]. It is generally accepted that breast cancer tumour cells are organized in a hierarchical fashion and that small subpopulations of cancer stem cells (CSCs) are actively resident within all tumour subtypes. CSCs are endowed with the capacity for self-renewal and multi-lineage differentiation, tumourigenicity, invasiveness and therapeutic resistance, all features that facilitate tumour progression, disease recurrence, and metastasis [2-4]. Specific therapeutic targeting of small CSC subpopulations is challenging but could have profound and long lasting clinical benefits for patients. Several methods of functional enrichment for CSCs have been utilized to facilitate better understanding and characterization of these subpopulations [5-7]. As a result, numerous genes and cell surface markers have already been associated with CSC-like functional behaviour within various breast cancer subtypes [4,8,9], however, a common marker of CSC subpopulations remains to be clearly defined. The "reprogramming of energy metabolism" is a recognized hallmark of cancer, whereby tumour cells can adapt their cellular metabolism to satisfy the bioenergetic and biosynthetic requirements for sustained growth and proliferation [10-12]. Tumour cells undergo a metabolic switch from aerobic, oxidative metabolism to high levels of aerobic glycolysis [13]. As a result, the oxidative phosphorylation reaction remains incomplete and leads to increased export of acetyl-CoA from the mitochondria into the cytosol. Cytosolic acetyl-CoA molecules are building blocks for lipogenic and anabolic reactions to promote cell growth and proliferation [14]. In breast cancer, the mevalonate metabolic pathway for cholesterol biogenesis and protein prenylation has been implicated with tumour cell transformation, malignancy and the specific regulation of basal-derived CSCs [15-17]. Furthermore, pharmacological blockades of the mevalonate pathway using statin or nitrogen-containing bisphosphonate therapeutics reduced the self-renewal capacity of the basal-derived CSCs, tumour cell motility, osteolytic bone lesions and the risk of breast cancer recurrence [16,18-20].

The purpose of this study was to utilize transcriptome-wide screening of CSC subpopulations to elucidate any signalling networks that may be actively up-regulated independent of explicit breast cancer subtypes. The mevalonate pathway was identified and single-cell gene expression profiling was applied to better characterize the pathway in models of luminal and basal breast cancer. This data highlighted the mevalonate precursor enzyme, 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), whose up-regulation is a common transcriptional event in CSC-enriched subpopulations of breast cancer cell lines. HMGCS1 catalyses the chemical conversion of acetoacetyl-CoA present within the cytosol to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), which is the chemical structure necessary for HMG-CoA to successfully enter and initiate the mevalonate pathway [14,21]. HMGCS1 was further investigated as an independent entity and its effects on functional CSC-enrichment and CSC-associated genetic signatures were studied using transient knockdown systems and single-cell analysis. Importantly, in our experimental models, inhibition of HMGCS1...

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Gale Document Number: GALE|A630130149