title: Squalene epoxidase is a bona fide oncogene by amplification with clinical relevance in breast cancer.
abstract: SQLE encodes squalene epoxidase, a key enzyme in cholesterol synthesis. SQLE has sporadically been reported among copy-number driven transcripts in multi-omics cancer projects. Yet, its functional relevance has never been subjected to systematic analyses. Here, we assessed the correlation of SQLE copy number (CN) and gene expression (GE) across multiple cancer types, focusing on the clinico-pathological associations in breast cancer (BC). We then investigated whether any biological effect of SQLE inhibition could be observed in BC cell line models. Breast, ovarian, and colorectal cancers showed the highest CN driven GE among 8,783 cases from 22 cancer types, with BC presenting the strongest one. SQLE overexpression was more prevalent in aggressive BC, and was an independent prognostic factor of unfavorable outcome. Through SQLE pharmacological inhibition and silencing in a panel of BC cell lines portraying the diversity of SQLE CN and GE, we demonstrated that SQLE inhibition resulted in a copy-dosage correlated decrease in cell viability, and in a noticeable increase in replication time, only in lines with detectable SQLE transcript. Altogether, our results pinpoint SQLE as a bona fide metabolic oncogene by amplification, and as a therapeutic target in BC. These findings could have implications in other cancer types.
authors.affiliation: J.-C. Heuson Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels BE.
authors.forename: David N
authors.initials: DN
authors.lastname: Brown
authors.affiliation: Department of Internal Medicine (Di.M.I.), University of Genova, Genova IT.
authors.forename: Irene
authors.initials: I
authors.lastname: Caffa
authors.affiliation: Department of Internal Medicine (Di.M.I.), University of Genova, Genova IT.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Cirmena
authors.affiliation: Department of Internal Medicine (Di.M.I.), University of Genova, Genova IT.
authors.forename: Daniela
authors.initials: D
authors.lastname: Piras
authors.affiliation: Department of Internal Medicine (Di.M.I.), University of Genova, Genova IT.
authors.forename: Anna
authors.initials: A
authors.lastname: Garuti
authors.affiliation: Department of Internal Medicine (Di.M.I.), University of Genova, Genova IT.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Gallo
authors.affiliation: Unità di Patologia Oncologica CeSI, Università "G. D'Annunzio", Chieti Scalo (Chieti) IT.
authors.forename: Saverio
authors.initials: S
authors.lastname: Alberti
authors.affiliation: Department of Internal Medicine (Di.M.I.), University of Genova, Genova IT.|Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera-Universitaria San Martino and National Cancer Institute, Genova IT.
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
authors.affiliation: Department of Internal Medicine (Di.M.I.), University of Genova, Genova IT.|Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera-Universitaria San Martino and National Cancer Institute, Genova IT.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ballestrero
authors.affiliation: Department of Internal Medicine (Di.M.I.), University of Genova, Genova IT.|Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera-Universitaria San Martino and National Cancer Institute, Genova IT.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Zoppoli
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002898:Chromosomes, Human, Pair 8; D056915:DNA Copy Number Variations; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D020868:Gene Silencing; D016259:Genes, myc; D056426:Genetic Loci; D006801:Humans; D060787:Neoplasm Grading; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D063868:Patient Outcome Assessment; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D050603:Squalene Monooxygenase / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D050603:Squalene Monooxygenase