Dermcidin exerts its oncogenic effects in breast cancer via modulation of ERBB signaling.

Abstract

BACKGROUND:

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 therefore searched for specific molecular signatures in DCD-positive breast carcinomas from patients and representative cell lines.

METHODS:

DCD 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.

RESULTS:

We 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.

CONCLUSIONS:

These 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.

• Authors: Jasna Bancovik, Dayson F Moreira, Daniel Carrasco, Jun Yao, Dale Porter, Ricardo Moura, Anamaria Camargo, Cibely C Fontes-Oliveira, Miguel G Malpartida, Silvia Carambula, Edouard Vannier, Bryan E Strauss, Alda Wakamatsu, Venancio Af Alves, Angela F Logullo, Fernando A Soares, Kornelia Polyak, José E Belizário
• Journal: BMC cancer (BMC Cancer) Vol. 15 Pg. 70 (Feb 19 2015) ISSN: 1471-2407 [Electronic] England
• PMID: 25879571 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers
• Dermcidins
• Receptor, ErbB-2
• Trastuzumab

Topics

• Alternative Splicing
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Biomarkers
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics, metabolism)
• Cluster Analysis
• Dermcidins (genetics, metabolism)
• Disease Models, Animal
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Heterografts
• Humans
• Immunohistochemistry
• Receptor, ErbB-2 (antagonists & inhibitors, metabolism)
• Signal Transduction
• Trastuzumab (administration & dosage, pharmacology)
• Tumor Burden (drug effects)