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
AuthorsWalsh, C. A.
AffiliationSahlgrenska Cancer Center, Department of Laboratory Medicine, Gothenburg, Sweden.
MetadataShow full item record
AbstractThe 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.
CitationWalsh CA, Akrap N, Garre E, Magnusson Y, Harrison H, Andersson D, et al. 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. PloS one. 2020;15(7):e0236187.
- Mevalonate metabolism regulates Basal breast cancer stem cells and is a potential therapeutic target.
- Authors: Ginestier C, Monville F, Wicinski J, Cabaud O, Cervera N, Josselin E, Finetti P, Guille A, Larderet G, Viens P, Sebti S, Bertucci F, Birnbaum D, Charafe-Jauffret E
- Issue date: 2012 Jul
- Genome-wide RNAi analysis reveals that simultaneous inhibition of specific mevalonate pathway genes potentiates tumor cell death.
- Authors: Pandyra AA, Mullen PJ, Goard CA, Ericson E, Sharma P, Kalkat M, Yu R, Pong JT, Brown KR, Hart T, Gebbia M, Lang KS, Giaever G, Nislow C, Moffat J, Penn LZ
- Issue date: 2015 Sep 29
- Cancer stem cell markers are associated with adverse biomarker profiles and molecular subtypes of breast cancer.
- Authors: Tsang JY, Huang YH, Luo MH, Ni YB, Chan SK, Lui PC, Yu AM, Tan PH, Tse GM
- Issue date: 2012 Nov
- The isomiR-140-3p-regulated mevalonic acid pathway as a potential target for prevention of triple negative breast cancer.
- Authors: Bhardwaj A, Singh H, Trinidad CM, Albarracin CT, Hunt KK, Bedrosian I
- Issue date: 2018 Dec 11
- HMG-CoA synthase 1 is a synthetic lethal partner of BRAF<sup>V600E</sup> in human cancers.
- Authors: Zhao L, Fan J, Xia S, Pan Y, Liu S, Qian G, Qian Z, Kang HB, Arbiser JL, Pollack BP, Kudchadkar RR, Lawson DH, Rossi M, Abdel-Wahab O, Merghoub T, Khoury HJ, Khuri FR, Boise LH, Lonial S, Chen F, Chen J, Lin R
- Issue date: 2017 Jun 16