title: High expression of cholesterol biosynthesis genes is associated with resistance to statin treatment and inferior survival in breast cancer.
abstract: There is sufficient evidence that statins have a protective role against breast cancer proliferation and recurrence, but treatment predictive biomarkers are lacking. Breast cancer cell lines displaying diverse sensitivity to atorvastatin were subjected to global transcriptional profiling and genes significantly altered by statin treatment were identified. Atorvastatin treatment strongly inhibited proliferation in estrogen receptor (ER) negative cell lines and a commensurate response was also evident on the genome-wide transcriptional scale, with ER negative cells displaying a robust deregulation of genes involved in the regulation of cell cycle progression and apoptosis. Interestingly, atorvastatin upregulated genes involved in the cholesterol biosynthesis pathway in all cell lines, irrespective of sensitivity to statin treatment. However, the level of pathway induction; measured as the fold change in transcript levels, was inversely correlated to the effect of statin treatment on cell growth. High expression of cholesterol biosynthesis genes before treatment was associated with resistance to statin therapy in cell lines and clinical biopsies. Furthermore, high expression of cholesterol biosynthesis genes was independently prognostic for a shorter recurrence-free and overall survival, especially among ER positive tumors. Dysregulation of cholesterol biosynthesis is therefore predictive for both sensitivity to anti-cancer statin therapy and prognosis following primary breast cancer diagnosis.
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Siker
authors.initials: S
authors.lastname: Kimbung
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Barbara
authors.initials: B
authors.lastname: Lettiero
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Feldt
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.|Department of Oncology, Skåne University Hospital, Lund, Sweden.
authors.forename: Ana
authors.initials: A
authors.lastname: Bosch
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.|Department of Oncology, Skåne University Hospital, Lund, Sweden.
authors.forename: Signe
authors.initials: S
authors.lastname: Borgquist
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D000069059:Atorvastatin / Q000494:pharmacology*; D053898:Biosynthetic Pathways / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D061986:MCF-7 Cells; D011960:Receptors, Estrogen / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011960:Receptors, Estrogen; D002784:Cholesterol; D000069059:Atorvastatin
keywords: breast cancer; cholesterol biosynthesis; predictive biomarker; prognosis; statin