title: Association between CLN3 (Neuronal Ceroid Lipofuscinosis, CLN3 Type) Gene Expression and Clinical Characteristics of Breast Cancer Patients.
abstract: Breast cancer is the most common cancer in women worldwide. Elucidation of underlying biology and molecular pathways is necessary for improving therapeutic options and clinical outcomes. CLN3 protein (CLN3p), deficient in neurodegenerative CLN3 disease is anti-apoptotic, and defects in the CLN3 gene cause accelerated apoptosis of neurons in CLN3 disease and up-regulation of ceramide. Dysregulated apoptotic pathways are often implicated in the development of the oncogenic phenotype. Predictably, CLN3 mRNA expression and CLN3 protein were up-regulated in a number of human and murine breast cancer-cell lines. Here, we determine CLN3 expression in non-tumor vs. tumor samples from fresh and formalin-fixed/paraffin-embedded (FFPE) breast tissue and analyze the association between CLN3 overexpression and different clinicopathological characteristics of breast cancer patients. Additionally, gene expression of 28 enzymes involved in sphingolipid metabolism was determined. CLN3 mRNA is overexpressed in tumor vs. non-tumor breast tissue from FFPE and fresh samples, as well as in mouse MCF7 breast cancer compared to MCF10A normal cells. Of the clinicopathological characteristics of tumor grade, age, menopause status, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), only absence of HER2 expression correlated with CLN3 overexpression. Sphingolipid genes for ceramide synthases 2 and 6 (CerS2; CerS6), delta(4)-desaturase sphingolipid 2 (DEGS2), and acidic sphingomyelinase (SMPD1) displayed higher expression levels in breast cancer vs. control tissue, whereas ceramide galactosyltransferase (UGT8) was underexpressed in breast cancer samples. CLN3 may be a novel molecular target for cancer drug discovery with the goal of modulation of ceramide pathways.
authors.affiliation: Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center , Beirut , Lebanon.
authors.forename: Joelle
authors.initials: J
authors.lastname: Makoukji
authors.affiliation: Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center , Beirut , Lebanon.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Raad
authors.affiliation: Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center , Beirut , Lebanon.
authors.forename: Katia
authors.initials: K
authors.lastname: Genadry
authors.affiliation: Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center , Beirut , Lebanon.
authors.forename: Sally
authors.initials: S
authors.lastname: El-Sitt
authors.affiliation: Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center , Beirut , Lebanon.
authors.forename: Nadine J
authors.initials: NJ
authors.lastname: Makhoul
authors.affiliation: Department of Radiology, University of Iowa Hospitals and Clinics , Iowa City, IA , USA.
authors.forename: Ehab
authors.initials: E
authors.lastname: Saad Aldin
authors.affiliation: Department of Internal Medicine, American University of Beirut Medical Center , Beirut , Lebanon.
authors.forename: Eden
authors.initials: E
authors.lastname: Nohra
authors.affiliation: Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center , Beirut , Lebanon.
authors.forename: Mark
authors.initials: M
authors.lastname: Jabbour
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London , London , UK.
authors.forename: Ajanthah
authors.initials: A
authors.lastname: Sangaralingam
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London , London , UK.
authors.forename: Claude
authors.initials: C
authors.lastname: Chelala
authors.affiliation: Outcomes Research Unit, American University of Beirut Medical Center , Beirut , Lebanon.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Habib
authors.affiliation: Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center , Beirut , Lebanon.
authors.forename: Fouad
authors.initials: F
authors.lastname: Boulos
authors.affiliation: Department of Internal Medicine, American University of Beirut Medical Center , Beirut , Lebanon.
authors.forename: Arafat
authors.initials: A
authors.lastname: Tfayli
authors.affiliation: Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center , Beirut , Lebanon ; Neurogenetics Program, Division of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center , Beirut , Lebanon.
authors.forename: Rose-Mary
authors.initials: RM
authors.lastname: Boustany
keywords: CLN3; HER2; breast cancer; ceramide; sphingolipid signaling