title: MUC1-C oncoprotein confers androgen-independent growth of human prostate cancer cells.
abstract: BACKGROUND
  The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features. However, few insights are available regarding the functional role of MUC1 in prostate cancer.
  
  
  METHODS
  Effects of MUC1-C on androgen receptor (AR) expression were determined by RT-PCR, immunoblotting and AR promoter activation. Coimmunoprecipitations, direct binding assays, and chromatin immunoprecipitation (ChIP) studies were performed to assess the interaction between MUC1-C and AR. Cells were analyzed for invasion, growth in androgen-depleted medium, and sensitivity to MUC1-C inhibitors.
  
  
  RESULTS
  The present studies in androgen-dependent LNCaP and LAPC4 prostate cancer cells demonstrate that the oncogenic MUC1-C subunit suppresses AR expression. The results show that MUC1-C activates a posttranscriptional mechanism involving miR-135b-mediated downregulation of AR mRNA levels. The results further demonstrate that MUC1-C forms a complex with AR through a direct interaction between the MUC1-C cytoplasmic domain and the AR DNA-binding domain (DBD). In addition, MUC1-C associates with AR in a complex that occupies the PSA promoter. The interaction between MUC1-C and AR is associated with induction of the epithelial-mesenchymal transition (EMT) and increased invasion. MUC1-C also conferred growth in androgen-depleted medium and resistance to bicalutamide treatment. Moreover, expression of MUC1-C resulted in sensitivity to the MUC1-C inhibitor GO-203 with inhibition of growth in vitro. GO-203 treatment also inhibited growth of established tumor xenografts in nude mice.
  
  
  CONCLUSIONS
  These findings indicate that MUC1-C suppresses AR expression in prostate cancer cells and confers a more aggressive androgen-independent phenotype that is sensitive to MUC1-C inhibition.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.forename: Rehan
authors.initials: R
authors.lastname: Ahmad
authors.forename: Caining
authors.initials: C
authors.lastname: Jin
authors.forename: Maya Datt
authors.initials: MD
authors.lastname: Joshi
authors.forename: Minakshi
authors.initials: M
authors.lastname: Guha
authors.forename: Maroof
authors.initials: M
authors.lastname: Alam
authors.forename: Surender
authors.initials: S
authors.lastname: Kharbanda
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000728:Androgens / Q000378:metabolism*; D049109:Cell Proliferation; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D058990:Molecular Targeted Therapy; D018396:Mucin-1 / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000728:Androgens; C544965:MIRN135 microRNA, human; C060192:MUC1 protein, human; D035683:MicroRNAs; D018396:Mucin-1; D012333:RNA, Messenger; D011944:Receptors, Androgen