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  • Nanaomycin A The essential autophagy gene beclin BECN

    2018-11-13

    The essential autophagy gene beclin 1 (BECN1) is a haploinsufficient tumor suppressor (Liang et al., 1999; Qu et al., 2003; Yue et al., 2003) that is also located on the breast cancer tumor susceptibility chromosomal locus 17q21, ~150kb centromeric to BRCA1 (Aita et al., 1999). Monoallelic loss of BECN1 has been observed in about 40% of human breast cancers (Aita et al., 1999; Li Nanaomycin A et al., 2010), and enforced expression of BECN1 in breast cancer Nanaomycin A with allelic loss of 17q21 inhibits proliferation and tumorigenesis (Liang et al., 1999). Heterozygous deletion of BECN1 in mice leads to an increased incidence of spontaneous carcinomas (Qu et al., 2003; Yue et al., 2003), including breast carcinoma with basal-like features (Cicchini et al., 2014). Given the likely roles of both BRCA1 and BECN1 in the development of mammary malignancy and the close proximity of BRCA1 and BECN1 genes on chromosome 17q21, large genomic deletions of the 17q21 locus could increase the risk of sporadic breast cancer through loss of expression of both genes, or alternatively, through the loss of only one gene, with loss of the other representing a bystander effect (Laddha et al., 2014). Therefore, we sought to determine the importance of loss of BECN1 and of BRCA1 expression in women with ER-negative subtypes of breast cancer.
    Methods
    Results
    Discussion As expected due to their close proximity on chromosome 17q21, BECN1 and BRCA1 are often concordantly deleted or amplified in breast cancers. However, our findings indicate that decreased BECN1 (but not decreased BRCA1) expression characterizes breast cancers that have aggressive molecular and clinical characteristics. When compared with tumors with high levels of expression, tumors with low BECN1 expression were more likely to have a higher histological grade, TP53 mutations, HER2-enriched or basal-like intrinsic subtypes, triple-negative status, and worse survival. In contrast, the levels of BRCA1 expression did not distinguish tumors with these aggressive characteristics or unfavorable prognosis. Furthermore, in tumors with deletion of BRCA1, levels of BECN1 expression provided important additional discriminatory information; however, in tumors with deletion of BECN1, levels of BRCA1 expression did not distinguish the molecular and clinical features of tumors. Importantly, these relationships were observed across two independent regional databases with different expression analysis platforms (RNA-seq and microarray), suggesting that our results cannot be explained by population differences or idiosyncrasies in the characterization of tumors. Our findings are consistent with earlier studies of BECN1 in small cohorts of patients with breast cancer. Levels of BECN1 mRNA expression have been reported to be reduced in breast cancer (Li et al., 2010; T. Wu et al., 2012) and have been associated with poor differentiation, and increased tumor size, proliferation and risk of metastasis (T. Wu et al., 2012; Yao et al., 2011). In small datasets, low BECN1 mRNA expression was associated with triple-negative breast cancer (Cicchini et al., 2014) and with worse prognosis regardless of ER status (Perou et al., 2000; Dong et al., 2013). In addition, BECN1 DNA copy number loss has been reported to be associated with HER2 amplification and TP53 mutations (Negri et al., 2010). One previous analysis of TCGA dataset by Laddha et al. (2014) reported deletions of BRCA1 alone but not BECN1 alone in human breast cancer. That study, however, used an ad hoc heuristic approach for identifying deletions; our analyses of copy number variations based on the more rigorous GISTIC method could not confirm this earlier report. In fact, in METABRIC, BECN1 alone deletions were more common than BRCA1 deletions, indicating a further lack of confirmation of the findings of Laddha et al. In addition, Laddha et al. reported that there were no changes in the mean level of BECN1 mRNA expression in breast tumor samples versus normal tissue. However, the validity of this comparison is difficult to assess, since epithelial cells (which have very high levels of BECN1 expression) comprise the majority of cells in tumor samples but only a small proportion of cells in normal breast tissue. Most importantly, Laddha et al. considered human breast cancer to be a homogenous disease and did not analyze the relationship between BECN1 mRNA expression and specific clinical and pathological features of breast cancer. Our analyses of two large datasets, TCGA and METABRIC, revealed a marked association between low BECN1 expression and ER-negative breast cancers subtypes with aggressive clinical features.