Abstract
BackgroundBeclin 1, an important autophagy-related protein in human cells, is involved in cell death and cell survival. Beclin 1 mapped to human chromosome 17q21. It is widely expressed in normal mammary epithelial cells. Although down-regulated expression with mono-allelic deletions of beclin 1 gene was frequently observed in breast tumors, whether there was other regulatory mechanism of beclin 1 was to be investigated. We studied the expression of beclin 1 and explored the possible regulatory mechanisms on its expression in breast tumors.Methods20 pairs of tumors and adjacent normal tissues from patients with sporadic breast invasive ductal cancer (IDCs) were collected. The mRNA expression of beclin 1 was detected by real-time quantitative RT-PCR. Loss of heterozygosity (LOH) was determined by real-time quantitative PCR and microsatellite methods. The protein expression of beclin 1, p53, BRCA1 and BRCA2 was assessed by immunohistochemistry. CpG islands in 5' genomic region of beclin 1 gene were identified using MethylPrimer Program. Sodium bisulfite sequencing was used in examining the methylation status of each CpG island.ResultsDecreased beclin 1 mRNA expression was detected in 70% of the breast tumors, and the protein levels were co-related to the mRNA levels. Expression of beclin 1 mRNA was demonstrated to be much higher in the BRCA1 positive tumors than that in the BRCA1 negative ones. Loss of heterozygosity was detected in more than 45% of the breast tumors, and a dense cluster of CpG islands was found from the 5' end to the intron 2 of the beclin 1 gene. Methylation analysis showed that the promoter and the intron 2 of beclin 1 were aberrantly methylated in the tumors with decreased expression.ConclusionsThese data indicated that LOH and aberrant DNA methylation might be the possible reasons of the decreased expression of beclin 1 in the breast tumors. The findings here shed some new light on the regulatory mechanisms of beclin 1 in breast cancer.
Highlights
Beclin 1, an important autophagy-related protein in human cells, is involved in cell death and cell survival
It has been reported that reduced levels of beclin 1 expression and mono-allelic deletion were observed in human breast cancer cell lines and tissues [9]
The numbers show the mean values of beclin 1/b-actin mRNA expression and standard deviation in 20 breast tumors and adjacent normal tissues
Summary
Beclin 1, an important autophagy-related protein in human cells, is involved in cell death and cell survival. Autophagy is a process of cellular protein degradation through the autophagosomic-lysosomal pathway, which plays an important role in cell differentiation and maintenance of cellular homeostasis. It is usually defective in tumor cells [1,2]. Beclin 1, the mammalian orthologue of the yeast Atg6/Vps gene, is the first identified tumor suppressor gene in human to mediate autophagy [3,4] It was originally isolated by a yeasttwo-hybrid screen and its protein was identified as an interacting partner of Bcl-2, an important anti-apoptosis protein [5]. It has been reported that reduced levels of beclin 1 expression and mono-allelic deletion were observed in human breast cancer cell lines and tissues [9]. Whether there are other mechanisms for the loss of beclin 1 expression in breast cancer remains to be determined
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