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.

Claire A Walsh,Elena Garre,Adrian Harris,Daniel Andersson,Emma Jonasson,Jiannis Ragoussis,Nina Akrap,Göran Landberg,Svanheidur Rafnsdottir,Hannah Harrison,Francesca Buffa,Ylva Magnusson,Hani Choudhry,Anders Ståhlberg,Nehad M Alajez

doi:10.1371/journal.pone.0236187

Abstract

The definitive characterization of common cancer stem cell (CSCs) subpopulations in breast cancer subtypes with distinct genotypic and phenotypic features remains an ongoing challenge. In this study, we have used a non-biased genome wide screening approach to identify transcriptional networks that may be specific to the CSC subpopulations in both luminal and basal breast cancer subtypes. In depth studies of three CSC-enriched breast cancer cell lines representing various subtypes of breast cancer revealed a striking hyperactivation of the mevalonate metabolic pathway in comparison to control cells. The upregulation of metabolic networks is a key feature of tumour cells securing growth and proliferative capabilities and dysregulated mevalonate metabolism has been associated with tumour malignancy and cellular transformation in breast cancer. Furthermore, accumulating evidence suggests that Simvastatin therapy, a mevalonate pathway inhibitor, could affect breast cancer progression and reduce breast cancer recurrence. When detailing the mevalonate pathway in breast cancer using a single-cell qPCR, we identified the mevalonate precursor enzyme, HMGCS1, as a specific marker of CSC-enriched subpopulations within both luminal and basal tumour subtypes. Down-regulation of HMGCS1 also decreased the CSC fraction and function in various model systems, suggesting that HMGCS1 is essential for CSC-activities in breast cancer in general. These data was supported by strong associations between HMGCS1 expression and aggressive features, such as high tumour grade, p53 mutations as well as ER-negativity in lymph node positive breast cancer. Importantly, loss of HMGCS1 also had a much more pronounced effect on CSC-activities compared to treatment with standard doses of Simvastatin. Taken together, this study highlights HMGCS1 as a potential gatekeeper for dysregulated mevalonate metabolism important for CSC-features in both luminal and basal breast cancer subtypes. Pharmacological inhibition of HMGCS1 could therefore be a superior novel treatment approach for breast cancer patients via additional CSC blocking functions.

Highlights

Breast cancer is a distinctly heterogeneous disease, characterized by a complex and dynamic tumour cell population and a highly plastic tumour microenvironment [1]
hydroxy3-methylglutaryl-CoA synthase 1 (HMGCS1), an important precursor to the first committed step of the mevalonate pathway, appeared to behave entirely independent from the other pathway members. It was together with SC4MOL one of the only nine genes significantly over-expressed in all three cancer stem cells (CSCs)-enriched cell lines in the original RNA-seq dataset (Fig 1G and 1A), making HMGCS1, independent of the mevalonate pathway, an intriguing candidate marker for functional CSC-enrichment, with potential relevance in both luminal and basal subtypes
There is increasing evidences that CSCs influences many key processes involved in breast cancer progression, including tumour initiation, promotion and metastasis [33]

Summary

Introduction

Breast cancer is a distinctly heterogeneous disease, characterized by a complex and dynamic tumour cell population and a highly plastic tumour microenvironment [1]. Numerous genes and cell surface markers have already been associated with CSC-like functional behaviour within various breast cancer subtypes [4, 8, 9], a common marker of CSC subpopulations remains to be clearly defined. 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 [15,16,17]. 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, 18,19,20]

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