Decreased BECN1 mRNA Expression in Human Breast Cancer is Associated With Estrogen Receptor-Negative Subtypes and Poor Prognosis

Hao Tang,Salwa Sebti,Rossella Titone,Yunyun Zhou,Ciro Isidoro,Theodora S Ross,Hanina Hibshoosh,Guanghua Xiao,Milton Packer,Yang Xie,Beth Levine

doi:10.1016/j.ebiom.2015.01.008

Abstract

Both BRCA1 and Beclin 1 (BECN1) are tumor suppressor genes, which are in close proximity on the human chromosome 17q21 breast cancer tumor susceptibility locus and are often concurrently deleted. However, their importance in sporadic human breast cancer is not known. To interrogate the effects of BECN1 and BRCA1 in breast cancer, we studied their mRNA expression patterns in breast cancer patients from two large datasets: The Cancer Genome Atlas (TCGA) (n=1067) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n=1992). In both datasets, low expression of BECN1 was more common in HER2-enriched and basal-like (mostly triple-negative) breast cancers compared to luminal A/B intrinsic tumor subtypes, and was also strongly associated with TP53 mutations and advanced tumor grade. In contrast, there was no significant association between low BRCA1 expression and HER2-enriched or basal-like subtypes, TP53 mutations or tumor grade. In addition, low expression of BECN1 (but not low BRCA1) was associated with poor prognosis, and BECN1 (but not BRCA1) expression was an independent predictor of survival. These findings suggest that decreased mRNA expression of the autophagy gene BECN1 may contribute to the pathogenesis and progression of HER2-enriched, basal-like, and TP53 mutant breast cancers.

Highlights

Estrogen-receptor (ER) negative breast cancer comprises 25–30% of all sporadic breast cancer and is characterized by advanced histological grade, aggressive clinical behavior, a high rate of metastasis to the brainAbbreviations: Beclin 1 (BECN1), beclin 1 autophagy related gene; BRCA1, breast cancer 1, early onset gene; TCGA, The Cancer Genome Atlas; METABRIC, Molecular Taxonomy of Breast Cancer International Consortium; HER2, human epidermal growth factor receptor 2; TP53, tumor protein p53 gene; ER, estrogen receptor; GISTIC, genomic identification of significant targets in cancer; PR, progesterone receptor; PAM50, 50-gene prediction analysis of microarray; ATG5, autophagy related 5 gene; BCL-2, B-cell CLL/lymphoma 2; EGFR, epidermal growth factor receptor; OR, oddsratio; CI, confidence interval; CNV, copy-number variation; LQ, low quartile; HQ, high quartile; NA, not available.⁎ Correspondence to: Y
BECN1 and BRCA1 were each deleted in approximately one-third of the breast tumors in both the TCGA and METABRIC datasets (BECN1 deletion in 34% in TCGA and 33% in METABRIC; BRCA1 deletion in 35% in TCGA and 27% in METABRIC) (Supplementary Table 2)
In a subgroup analysis of patients who were diploid for BECN1 and BRCA1, in both the TCGA and METABRIC datasets, we found that low BECN1 mRNA expression but not low BRCA1 mRNA expression was associated with HER2-enriched and basal-like tumor subtypes, TP53 mutations, and grade III tumors (Supplementary Table 5)

Summary

Introduction

Estrogen-receptor (ER) negative breast cancer comprises 25–30% of all sporadic breast cancer and is characterized by advanced histological grade, aggressive clinical behavior, a high rate of metastasis to the brain⁎ Correspondence to: Y. Based on molecular profiling (Yersal and Barutca, 2014; Sotiriou and Pusztai, 2009), these cancers generally fall into two subtypes: (1) HER2-enriched tumors (those with overexpression or amplification of human epidermal growth factor receptor 2 [HER2]) and (2) basal-like tumors (which generally do not express estrogen or progesterone receptors or HER2/neu, but have high levels of basal markers and/or epidermal growth factor receptor expression and a high rate of TP53 mutations) (Sorlie et al, 2001; Perou et al, 2000). Tang et al / EBioMedicine 2 (2015) 255–263 and Roskelley, 2003), and may be related to the frequent loss of heterozygosity at the breast cancer tumor susceptibility locus on chromosome 17q21 (Staff et al, 2003) and/or BRCA1 promoter hypermethylation (Birgisdottir et al, 2006) or increased expression of negative regulatory factors (Turner et al, 2007; Garcia et al, 2011; Z.Q. Wu et al, 2012)

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