Abstract
BackgroundWe previously identified dermicidin (DCD), which encodes a growth and survival factor, as a gene amplified and overexpressed in a subset of breast tumors. Patients with DCD-positive breast cancer have worse prognostic features. We therefore searched for specific molecular signatures in DCD-positive breast carcinomas from patients and representative cell lines.MethodsDCD expression was evaluated by qRT-PCR, immunohistochemical and immunoblot assays in normal and neoplastic tissues and cell lines. To investigate the role of DCD in breast tumorigenesis, we analyzed the consequences of its downregulation in human breast cancer cell lines using three specific shRNA lentiviral vectors. Genes up- and down-regulated by DCD were identified using Affymetrix microarray and analyzed by MetaCore Platform.ResultsWe identified DCD splice variant (DCD-SV) that is co-expressed with DCD in primary invasive breast carcinomas and in other tissue types and cell lines. DCD expression in breast tumors from patients with clinical follow up data correlated with high histological grade, HER2 amplification and luminal subtype. We found that loss of DCD expression led to reduced cell proliferation, resistance to apoptosis, and suppressed tumorigenesis in immunodeficient mice. Network analysis of gene expression data revealed perturbed ERBB signaling following DCD shRNA expression including changes in the expression of ERBB receptors and their ligands.ConclusionsThese findings imply that DCD promotes breast tumorigenesis via modulation of ERBB signaling pathways. As ERBB signaling is also important for neural survival, HER2+ breast tumors may highjack DCD’s neural survival-promoting functions to promote tumorigenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1022-6) contains supplementary material, which is available to authorized users.
Highlights
We previously identified dermicidin (DCD), which encodes a growth and survival factor, as a gene amplified and overexpressed in a subset of breast tumors
Expression of DCD and DCD splice variant (DCD-SV) in normal and neoplastic tissues While analyzing the expression of DCD by Reverse transcriptase polymerase chain reaction (RT-PCR) in various normal and neoplastic tissues and cell lines, we identified a larger transcript co-expressed with DCD
Betacellulin, amphiregulin, Epidermal growth factor receptor (EGFR) and c-Myc expression levels decreased in each of the three different DCD Short hairpin RNA (shRNA) expressing cell pools compared to control pLKO (Figure 4C, Additional file 4: Excel Spreadsheet 1, Additional file 5). To experimentally validate these predictions of network analysis studies, we analyzed the expression levels of all ERBB family members by real time PCR in control and DCD shRNA expressing cells (Figure 5A,B). These analyses indicated that the expression levels for EGFR, ERBB2, and ERBB3, and their ligands BTC, Epidermal growth factor receptor (EGF), Transforming growth factor-α (TGF-α), AREG, Heparin-binding EGF-like growth factor (HB-EGF), NGR1, and NGR4 were down-regulated, whereas the ERBB4 and ligands EREG and NGR2 were up-regulated in cells expressing DCD shRNAs
Summary
We previously identified dermicidin (DCD), which encodes a growth and survival factor, as a gene amplified and overexpressed in a subset of breast tumors. Patients with DCD-positive breast cancer have worse prognostic features. We searched for specific molecular signatures in DCD-positive breast carcinomas from patients and representative cell lines. Patients with DCD-positive breast cancer are more likely to have metastatic lymph nodes, larger tumors, and worse clinical outcome [1]. The 11 kDa fulllength DCD protein and proteolytic peptides derived from it have been proposed to have diverse biological functions, such as acting as a growth and survival factor in breast cancer [1] and in neural cells [10,11], displaying. A recent study demonstrated that DCD may function as a proteolytic enzyme which can cleave and activate the pro-MMP-9 matrix metalloproteinase and, may promote tumor cell invasion [16]
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