title: 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: Department of Pharmacology, Institute of Biomedical Sciences - University of São Paulo, Av Lineu Prestes 1524, 05508-900, São Paulo, SP, Brazil. jasnam@ibiss.bg.ac.rs.
authors: Jasna
authors: J
authors: Bancovik
authors: Department of Pharmacology, Institute of Biomedical Sciences - University of São Paulo, Av Lineu Prestes 1524, 05508-900, São Paulo, SP, Brazil. dmoreira@coh.org.
authors: Dayson F
authors: DF
authors: Moreira
authors: Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute - Harvard Medical School, 450 Brookline Ave. D740C, Boston, MA, 02215, USA. daniel_eduardo_carrasco@hotmail.com.
authors: Daniel
authors: D
authors: Carrasco
authors: Department of Neuro-Oncology Research, Division of Cancer Medicine, University of Texas - MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. JYao1@mdanderson.org.
authors: Jun
authors: J
authors: Yao
authors: Oncology Disease Area and Developmental and Molecular Pathways Group, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. dale.porter@novartis.com.
authors: Dale
authors: D
authors: Porter
authors: Ludwig Institute for Cancer Research- Hospital Sírio-Libanês, Rua Peixoto Gomide, 316, 7th floor, 01409-000, São Paulo, SP, Brazil. anamaria@compbio.ludwig.org.br.
authors: Ricardo
authors: R
authors: Moura
authors: Ludwig Institute for Cancer Research- Hospital Sírio-Libanês, Rua Peixoto Gomide, 316, 7th floor, 01409-000, São Paulo, SP, Brazil. anamaria@compbio.ludwig.org.br.
authors: Anamaria
authors: A
authors: Camargo
authors: Department of Pharmacology, Institute of Biomedical Sciences - University of São Paulo, Av Lineu Prestes 1524, 05508-900, São Paulo, SP, Brazil. ccristine@gmail.com.
authors: Cibely C
authors: CC
authors: Fontes-Oliveira
authors: Department of Pharmacology, Institute of Biomedical Sciences - University of São Paulo, Av Lineu Prestes 1524, 05508-900, São Paulo, SP, Brazil. hmgaray@usp.br.
authors: Miguel G
authors: MG
authors: Malpartida
authors: Division of Geographic Medicine & Infectious Diseases, Tufts Medical Center, 25 Harvard Street - Tupper 729, Boston, MA, 02111, USA. scarambula@gmail.com.
authors: Silvia
authors: S
authors: Carambula
authors: Division of Geographic Medicine & Infectious Diseases, Tufts Medical Center, 25 Harvard Street - Tupper 729, Boston, MA, 02111, USA. evannier@tuftsmedicalcenter.org.
authors: Edouard
authors: E
authors: Vannier
authors: The Cancer Institute of São Paulo, Av. Dr. Arnaldo, 251, 8th floor, 01246-000, Sao Paulo, SP, Brazil. bstrrauss@usp.br.
authors: Bryan E
authors: BE
authors: Strauss
authors: Department of Pathology - School of Medicine, University of São Paulo, Avenida Dr Enéas de Carvalho Aguiar, 155 - 10th floor, 05403-000, Sao Paulo, SP, Brazil. awakamatsu@uol.com.br.
authors: Alda
authors: A
authors: Wakamatsu
authors: Department of Pathology - School of Medicine, University of São Paulo, Avenida Dr Enéas de Carvalho Aguiar, 155 - 10th floor, 05403-000, Sao Paulo, SP, Brazil. venancio@uol.com.br.
authors: Venancio Af
authors: VA
authors: Alves
authors: Department of Pathology - Paulista School of Medicine, Federal University of São Paulo, Rua Sena Madureira, 1500, 04021-001, São Paulo, SP, Brazil. waitzberg.angela@gmail.com.
authors: Angela F
authors: AF
authors: Logullo
authors: Department of Pathology - AC Camargo Cancer Center, Rua Professor Antônio Prudente, 211, 01509-010, São Paulo, SP, Brazil. fasoares@me.com.
authors: Fernando A
authors: FA
authors: Soares
authors: Department of Medical Oncology, Dana-Farber Cancer Institute - Harvard Medical School, 450 Brookline Ave. D740C, Boston, MA, 02215, USA. Kornelia_Polyak@dfci.harvard.edu.
authors: Kornelia
authors: K
authors: Polyak
authors: Department of Pharmacology, Institute of Biomedical Sciences - University of São Paulo, Av Lineu Prestes 1524, 05508-900, São Paulo, SP, Brazil. jebeliza@usp.br.
authors: José E
authors: JE
authors: Belizário
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D016000:Cluster Analysis; D054805:Dermcidins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D000068878:Trastuzumab / Q000008:administration & dosage / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D054805:Dermcidins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab