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.
Highlights
Materials and MethodsGlobally, about 1.38 million women are diagnosed with breast cancer and 458,503 die from the disease every year [1]
Of the six clinicopathological parameters studied, Ceroid Lipofuscinosis 3 (CLN3) overexpression was significantly associated with absence of human epidermal growth factor receptor 2 (HER2) expression (p = 0.045) in patients with invasive ductal carcinomas (IDC) of the breast (Table 2)
Receptor status is used as a guide to classify breast cancers into four biological subtypes: (a) low grade luminal A subtype, (b) high grade luminal B subtype (High grade, ER/PR positive or HER2+/ER+/PR+), (c) HER2 subtype (HER2+/ER−/PR−), and (d) triple negative/basal like subtype (HER2−/ER−/PR−) [22]
Summary
Materials and MethodsGlobally, about 1.38 million women are diagnosed with breast cancer and 458,503 die from the disease every year [1]. CLN3 Gene Expression To determine the potential role of CLN3 in the development and progression of IDC of the breast, 75 paired fresh tumor tissues and 189 paired FFPE IDC breast samples were collected and Cancer vs normal tissue from same patient
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