DEC1 is positively associated with the malignant phenotype of invasive breast cancers and negatively correlated with the expression of claudin-1

Abstract

Abstract. Differentiated embryo-chondrocyte expressed gene 1 (DEC1) is a basic helix-loop-helix transcriptional regulator, reportedly involved in cell growth, differentiation, apoptosis and tumorigenesis. In breast cancer, DEC1 expression correlates with increased malignant potential and invasiveness. Nevertheless, the detailed mechanisms by which DEC1 modulates breast cancer progression are still unclear. Claudin-1, an important tight junction protein, functions as a tumor invasion suppressor. In the present study, the relationship between DEC1 and claudin-1 in 147 cases of invasive breast ductal carcinomas was examined by immunohistochemistry. Based on the data, DEC1 expression was elevated in invasive breast ductal carcinomas and DEC1 levels were positively correlated with tumor grade (P=0.023). Moreover, DEC1 expression was negatively correlated with the claudin-1 level (correlation coefficient =-0.245, P=0.003). We further identified that, in MCF-7 and MDA-MB-231 breast cancer cell lines, DEC1 knockdown led to the enhanced expression of claudin-1 at both the mRNA and protein levels, and reduced cell invasive capacity. Collectively, our data suggest that overexpression of DEC1 may promote the invasiveness of breast cancer through downregulation of claudin-1. IntroductionDifferentiated embryo-chondrocyte expressed gene 1 (DEC1, also known as BHLHE40/Stra13/Sharp2) is a basic helix-loophelix (bHLH) transcription factor ubiquitously expressed in both embryonic and adult tissues (1,2). DEC1 exerts multiple biological functions, such as neurogenesis, apoptosis, cell proliferation, cell differentiation and circadian rhythms (3-8). Recent studies have revealed that the expression of DEC1 is correlated with the malignancy of a number of cancer types (9). The expression patterns of DEC1 and their impact on tumor development are largely tumor-type specific (1,9). Low DEC1 expression was found to be associated with poor histological differentiation and malignancy progression in hepatocellular carcinoma (10), whereas, overexpression of DEC1 was significantly correlated with poor survival of patients with esophageal squamous cell carcinoma following surgery (11). In breast cancer, the expression of DEC1 was found to be increased upon progression from normal tissues to invasive carcinomas (12). However, the mechanisms by which DEC1 modulates cancer progression are largely unclear.Claudin-1 is a key component of the tight junction complex and is thereby important for maintaining tight junction barrier integrity. Downregulation of claudin-1 is intimately associated with tumorigenesis in breast (13,14), prostate (15) and melanocytic neoplasia (16). It is postulated that the impact of claudin-1 on cancer invasion and metastasis is through its regulation of certain invasion/metastasis suppressors or enhancers (17,18). As significant loss of claudin-1 expression and overexpression of DEC1 are commonly observed in the progression of various types of cancers including breast cancer, we aimed to ascertain whether DEC1 modulates br...

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