title: Mevalonate metabolism regulates Basal breast cancer stem cells and is a potential therapeutic target.
abstract: There is increasing evidence that breast tumors are organized in a hierarchy, with a subpopulation of tumorigenic cancer cells, the cancer stem cells (CSCs), which sustain tumor growth. The characterization of protein networks that govern CSC behavior is paramount to design new therapeutic strategies targeting this subpopulation of cells. We have sought to identify specific molecular pathways of CSCs isolated from 13 different breast cancer cell lines of luminal or basal/mesenchymal subtypes. We compared the gene expression profiling of cancer cells grown in adherent conditions to those of matched tumorsphere cultures. No specific pathway was identified to be commonly regulated in luminal tumorspheres, resulting from a minor CSC enrichment in tumorsphere passages from luminal cell lines. However, in basal/mesenchymal tumorspheres, the enzymes of the mevalonate metabolic pathway were overexpressed compared to those in cognate adherent cells. Inhibition of this pathway with hydroxy-3-methylglutaryl CoA reductase blockers resulted in a reduction of breast CSC independent of inhibition of cholesterol biosynthesis and of protein farnesylation. Further modulation of this metabolic pathway demonstrated that protein geranylgeranylation (GG) is critical to breast CSC maintenance. A small molecule inhibitor of the geranylgeranyl transferase I (GGTI) enzyme reduced the breast CSC subpopulation both in vitro and in primary breast cancer xenografts. We found that the GGTI effect on the CSC subpopulation is mediated by inactivation of Ras homolog family member A (RHOA) and increased accumulation of P27(kip1) in the nucleus. The identification of protein GG as a major contributor to CSC maintenance opens promising perspectives for CSC targeted therapy in basal breast cancer.
authors.affiliation: Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille, INSERM, Institut Paoli-Calmettes, 27 Boulevard Leï Roure, Marseille, France. christophe.ginestier@inserm.fr
authors.forename: Christophe
authors.initials: C
authors.lastname: Ginestier
authors.forename: Florence
authors.initials: F
authors.lastname: Monville
authors.forename: Julien
authors.initials: J
authors.lastname: Wicinski
authors.forename: Olivier
authors.initials: O
authors.lastname: Cabaud
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cervera
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Josselin
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.forename: Arnaud
authors.initials: A
authors.lastname: Guille
authors.forename: Gaelle
authors.initials: G
authors.lastname: Larderet
authors.forename: Patrice
authors.initials: P
authors.lastname: Viens
authors.forename: Said
authors.initials: S
authors.lastname: Sebti
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charafe-Jauffret
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D018295:Neoplasms, Basal Cell / Q000188:drug therapy / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D043823:Taxoids / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C102521:GGTI 298; D043823:Taxoids; D000077143:Docetaxel; D008798:Mevalonic Acid