Abstract
NDRG2, a member of the N-myc downstream-regulated gene family, is thought to be a putative tumor suppressor gene with promising clinical impact in breast cancer. Since breast cancer comprises heterogeneous intrinsic subtypes with distinct clinical outcomes we investigated the pivotal role of NDRG2 in basal-type breast cancers. Based on subtype classified tumor (n = 45) and adjacent normal tissues (n = 17) we examined NDRG2 mRNA expression and CpG-hypermethylation, whose significance was further validated by independent data sets from The Cancer Genome Atlas (TCGA). In addition, NDRG2 protein expression was evaluated immunohistochemically using a tissue micro array (TMA, n = 211). In vitro, we investigated phenotypic effects caused by NDRG2 silencing in the basal A-like HCC1806 as well as NDRG2 over-expression in basal A-like BT20 compared to luminal-type MCF7 breast cancer cells. Our tissue collections demonstrated an overall low NDRG2 mRNA expression in breast cancer subtypes compared to normal breast tissue in line with an increased CpG-hypermethylation in breast cancer tissue. Independent TCGA data sets verified a significant (P<0.001) expression loss of NDRG2 in breast tumors. Of interest, basal-like tumors more frequently retained abundant NDRG2 expression concordant with a lower CpG-hypermethylation. Unexpectedly, basal-like breast cancer revealed an association of NDRG2 expression with unfavorable patients’ outcome. In line with this observation, in vitro experiments demonstrated reduced proliferation and migration rates (~20%) in HCC1806 cells following NDRG2 silencing. In contrast, NDRG2 over-expressing luminal-type MCF7 cells demonstrated a 26% decreased proliferation rate. Until now, this is the first study investigating the putative role of NDRG2 in depth in basal-type breast cancer. Our data indicate that the described putative tumor suppressive function of NDRG2 may be confined to luminal- and basal B-type breast cancers.
Highlights
Breast cancer remains the most frequently diagnosed cancer and the leading cause of cancer deaths in European women [1]
We showed a significant (P
We revealed a pronounced downregulation of NDRG2 mRNA in luminal A- and luminal B-type breast cancer compared to triple negative (i.e. mammary tumors that lack receptors for estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER2)) cases (Fig 1A)
Summary
Breast cancer remains the most frequently diagnosed cancer and the leading cause of cancer deaths in European women [1]. Based on the high breast cancer-related mortality rate, the understanding of tumor biological and molecular consequences is mandatory, enabling an individual and targeted development of breast cancer therapy. Adapting current diagnostic and therapeutic strategies to each patient is a challenging task due to the heterogeneous molecular aspects of breast tumors. Breast cancer can be classified into four main intrinsic subtypes, i.e. luminal A, luminal B, HER2-enriched and basal-like, based upon global gene expression profiles demonstrated for the first time in 2000 by Perou and colleagues [2]. While patients with luminal A tumors benefit from systemic endocrine therapy, therapeutic targets for the basal-like class of breast cancer is still insufficient due to the lack of understanding of the driving oncogenic mechanisms [3], resulting in chemotherapy treatment. Breast cancer patients affected with basal-type cancer show worse survival outcome compared to patients with e.g. luminal A-type breast cancer [3]
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